Resolution of AP sites can occur through the single nucleotide replacement pathway or through the multiple nucleotide patch replacement pathway, also known as the long-patch base excision repair (BER). Except for the APEX1-independent resolution of AP sites via single nucleotide base excision repair mediated by NEIL1 or NEIL2 (Wiederhold et al. 2004, Das et al. 2006), single nucleotide and multiple-nucleotide patch replacement pathways are both initiated by APEX1-mediated displacement of DNA glycosylases and cleavage of the damaged DNA strand by APEX1 immediately 5' to the AP site (Wilson et al. 1995, Bennett et al. 1997, Masuda et al. 1998). The BER proceeds via the single nucleotide replacement when the AP (apurinic/apyrimidinic) deoxyribose residue at the 5' end of the APEX1-created single strand break (SSB) (5'dRP) can be removed by the 5'-exonuclease activity of DNA polymerase beta (POLB) (Bennett et al. 1997). POLB fills the created single nucleotide gap by adding a nucleotide complementary to the undamaged DNA strand to the 3' end of the SSB. The SSB is subsequently ligated by DNA ligase III (LIG3) which, in complex with XRCC1, is recruited to the BER site by an XRCC1-mediated interaction with POLB (Kubota et al. 1996). BER proceeds via the multiple-nucleotide patch replacement pathway when the AP residue at the 5' end of the APEX1-created SSB undergoes oxidation-related damage (5'ddRP) and cannot be cleaved by POLB (Klungland and Lindahl 1997). Long-patch BER can be completed by POLB-mediated DNA strand displacement synthesis in the presence of PARP1 or PARP2, FEN1 and DNA ligase I (LIG1) (Prasad et al. 2001). When the PCNA-containing replication complex is available, as is the case with cells in S-phase of the cell cycle, DNA strand displacement synthesis is catalyzed by DNA polymerase delta (POLD) or DNA polymerase epsilon (POLE) complexes, in the presence of PCNA, RPA, RFC, APEX1, FEN1 and LIG1 (Klungland and Lindahl 1997, Dianova et al. 2001). It is likely that the 9-1-1 repair complex composed of HUS1, RAD1 and RAD9 interacts with and coordinates components of BER, but the exact mechanism and timing have not been elucidated (Wang et al. 2004, Smirnova et al. 2005, Guan et al. 2007, Balakrishnan et al. 2009).
View original pathway at:Reactome.
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Base excision repair is initiated by DNA glycosylases that hydrolytically cleave the base-deoxyribose glycosyl bond of a damaged nucleotide residue, releasing the damaged base (Lindahl and Wood 1999, Sokhansanj et al. 2002).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces UNG from the AP site generated by UNG DNA glycosylase activity (Nicholl et al. 1997, Parikh et al. 1998, Akbari et al. 2004, Kuznetsova et al. 2014).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces TDG from the AP site created by the DNA glycosylase activity of TDG. In the absence of APEX1, TDG remains tightly bound to the AP site, which inhibits subsequent steps in the base excision repair. Sumoylation of TDG may also be involved in the APEX1-mediated displacement of TDG from AP sites (Hardeland et al. 2002, Steinacher and Schar 2005, Fitzgerald and Drohat 2008).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces SMUG1 from the AP site created by the SMUG1 DNA glycosylase activity (Pettersen et al. 2007).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces NTHL1 (hNTH1) from the AP site generated by the NTHL1 DNA glycosylase activity. Current data indicate that while the NTHL1 DNA lyase activity is blocked at most NTHL1-bound AP sites, it can act on the AP site generated by the thymine glycol cleavage (Marenstein et al. 2003).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces MBD4 (MED1) from the AP site generated by the MBD4 DNA glycosylase activity (Kuznetsova et al. 2014).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces OGG1 from the AP site generated by the OGG1 DNA glycosylase activity, thus allowing for the base excision repair to proceed (Hill et al. 2001, Kuznetsova et al. 2014).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic site lyase, displaces MUTYH (MYH) from the AP site generated by the MUTYH DNA glycosylase activity, thus increasing MUTYH turnover and overall glycosylase efficiency, and allowing for the base excision repair to proceed (Yang et al. 2001).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site lyase, displaces MPG from the AP site generated by the MPG DNA glycosylase activity, thus increasing MPG turnover and the overall glycosylase efficiency (Xia et al. 2005).
APEX1 (APE1, HAP1), a DNA apurinic/apyrimidinic (AP) site DNA lyase, cleaves the DNA strand sugar-phosphate backbone 5' to the AP site generated by DNA glycosylases or that forms by spontaneous loss of a base, producing a DNA strand with a 3'-terminal unsaturated sugar and a DNA strand with a terminal abasic 5'-deoxyribosephosphate (5'-dRP) as cleavage products (Wilson et al. 1995, Bennett et al. 1997, Masuda et al. 1998, Parikh et al. 1998).
APEX1 (APE1) bound to the apurinic/apyrimidinic site (AP site) in the DNA recruits DNA polymerase beta (POLB) into a ternary complex (Bennett et al. 1997).
PCNA-bound FEN1 acts as a flap endonuclease to cleave the displaced single strand DNA (flap) containing the oxidatively damaged AP (apurinic/apyrimidinic) dideoxyribose residue (5'ddRP) that could not be excised by POLB. Interaction between FEN1 and PCNA or FEN1 and APE1 facilitate cleavage of flap structures (Klungland and Lindahl 1997, Matsumoto et al. 1999, Dianov et al. 1999).
PCNA-dependent long-patch base excision repair (BER) occurs during the S phase of the cell cycle when PCNA and associated DNA polymerases are available. PCNA is part of a large replicative complex that contains DNA polymerase delta or DNA polymerase epsilon, along with RPA and RFC complexes. When POLB (DNA polymerase beta) is unable to excise the oxidatively damaged AP residue (5'ddRP) at the APEX1-generated single strand break (SSB), PCNA and FEN1 are recruited to APEX1, where PCNA interacts with both APEX1 (Dianova et al. 2001) and FEN1 (Tom et al. 2000, Shibata and Nakamura 2002). PCNA-bound DNA polymerase delta complex (POLD) or DNA polymerase epsilon complex (POLE) displaces DNA polymerase beta (POLB) from the SSB (Klungland and Lindahl 1997).
Polymerase delta complex (POLD) or polymerase epsilon complex (POLE) bound to PCNA-associated replication complex that also includes RPA and RFC complexes, catalyzes DNA strand displacement synthesis in a reaction facilitated by FEN1 and APEX1. POLD or POLE extend the 3' end of the single strand break (SSB) by adding up to 10 nucleotides. The 5' end of the SSB, which contains the oxidatively damaged AP (apurinic/apyrimidinic) dideoxyribose phosphate residue (5'ddRP) that could not be excised by POLB, is displaced as a flap structure by the joint action of FEN1 and POLD or POLE (Klungland and Lindahl 1997, Stucki et al. 1998, Dianov et al. 1999, Podlutsky et al. 2001, Ranalli et al. 2002).
LIG1 (DNA ligase I) is recruited to the long-patch base excision repair site through direct interaction with APEX1 (Ranalli et al. 2002), PCNA (Montecucco et al. 1998, Levin et al. 2000) and RFC (Vijayakumar et al. 2009). The binding of LIG1 to RFC is negatively regulated by LIG1 phosphorylation (Vijaykumar et al. 2009, Peng et al. 2012).
After incision of the DNA strand 5' to the apurinic/apyrimidinic (AP) site by APEX1 (APE1), POLB (DNA polymerase beta) excises the 5'-terminal abasic deoxyribose phosphate (5'-dRP), thus removing the AP site (Bennet et al. 1997).
After abasic (AP) residue (5'dRP) is excised by POLB, which is accompanied by dissociation of APEX1 from the DNA, POLB recruits XRCC1:LIG3 complex, consisting of DNA repair protein XRCC1 and DNA ligase 3, to the DNA containing a single nucleotide gap (Nazarkina et al. 2007). The N-terminus of XRCC1 interacts with POLB, while the C-terminus of XRCC1 interacts with LIG3 (Kubota et al. 1996).
After the base excision repair is completed, the complex of XRCC1 with LIG3 (DNA ligase 3), and POLB (DNA polymerase beta) dissociate from the repaired DNA (Kubota et al. 1997).
DNA polymerase beta (POLB) cannot excise oxidatively damaged 5' AP (apurinic/apyrimidinic) dideoxyribose residue (5'ddRP) at the APEX1-generated single strand break (SSB). Instead, POLB incorporates the first nucleotide (dNMP) at the 3' end of the SSB, which displaces 5'ddRP (Podlutsky et al. 2001).
Although NEIL1 and NEIL2 have a weak 8-oxoguanine glycosylase activity, NEIL1 (and probably NEIL2) enhance OGG1 efficiency against 8-oxogunanine by displacing OGG1 from created AP (apurinic/apyrimidinic) sites and thereby increasing OGG1 turnover (Wiederhold et al. 2004, Hazra et al. 2002a and 2002b).
PNKP, a bifunctional polynucleotide phosphatase/kinase, acts as a 3' phosphatase to remove the terminal 3' phosphate group (3'Pi) at the single strand break (SSB) generated by NEIL1 or NEIL2 beta/delta lyase activity. The presence of XRCC1 is necessary for the 3'-phosphatase activity of PNKP. The removal of the 3'Pi (generating a 3'-OH) makes the DNA with the 3'-end suitable for extension by the DNA polymerase beta (POLB) (Whitehouse et al. 2001, Wiederhold et al. 2004, Das et al. 2006).
DNA polymerase beta (POLB) is recruited to the AP (apurinic/apyrimidinic) site incised by the lyase activity of NEIL1 or NEIL2. The C-terminus of NEIL1 binds the N-terminus of POLB, while the N-terminus of NEIL2 is involved in the interaction with POLB (Wiederhold et al. 2004, Das et al. 2006).
NEIL1 or NEIL2 bound to AP-dsDNA (DNA with apurinic/apyrimidinic site) act as beta/delta lyases to cleave the AP-site containing DNA strand 5' to the AP site, thus producing DNA strand with a terminal 3' phosphate (3'Pi) and a DNA strand with a terminal 5'-deoxyribosephosphate (5'dRP) (Wiederhold et al. 2004, Das et al. 2006).
POLB (DNA polymerase beta) incorporates a single nucleotide to extend the PNKP-processed 3' end of the single strand break (SSB) generated by the beta/delta lyase activity of NEIL1 or NEIL2. POLB thus replaces the excised AP (apurinic/apyrimidinic) deoxyribose phosphate residue (5'dRP) (Wiederhold et al. 2004, Das et al. 2006).
After the completion of the base excision repair (BER), NEIL1 or NEIL2, POLB, LIG3:XRCC1 and PNKP dissociate from repaired DNA (Wiederhold et al. 2004, Das et al. 2006).
POLB (DNA polymerase beta) acts as a 5'-exonuclease to remove the abasic deoxyribose residue (5'dRP) generated by the DNA glycosylase and/or beta/delta lyase activity of NEIL1 or NEIL2, producing a single nucleotide gap at the SSB (single strand break) site (Wiederhold et al. 2004, Das et al. 2006). The NEIL1 or NEIL2-generated SSB has a 3' terminal phosphate (3'Pi).
LIG3:XRCC1, a complex of DNA ligase 3 and DNA repair protein XRCC1, is recruited to the single nucleotide gap at the SSB (single strand break) site bound by NEIL1 or NEIL2, and POLB, along with polynucleotide kinase/phosphatase PNKP. A large complex containing NEIL1 or NEIL2, PNKP, POLB, LIG3 and XRCC1 can be co-immunoprecipitated from cells undergoing NEIL1 or NEIL2-mediated base excision repair via single nucleotide replacement. NEIL1 interacts with POLB and LIG3 directly, but not with PNKP or XRCC1 (Wiederhold et al. 2004, Das et al. 2006). PNKP directly binds XRCC1, LIG3 and POLB, and the interaction with XRCC1 is essential for the 3'-phosphatase activity of PNKP (Whitehouse et al. 2001).
After POLB (DNA polymerase beta) fills the single nucleotide gap created by the NEIL1 or NEIL2 and POLB-mediated excision of the apurinic/apyrimidinic (AP) site in a damaged DNA strand, LIG3 (DNA ligase 3) ligates the two DNA strand fragments at the single strand break (SSB), thus completing the base excision repair (Wiederhold et al. 2004, Das et al. 2006).
APEX1 (APE1) bound to oxidatively damaged 5' AP (apurinic/apyrimidinic) dideoxyribose site (5'ddRP) recruits DNA polymerase beta (POLB) (Matsumoto et al. 1994, Klungland and Lindahl 1997, Bennett et al. 1997).
The APEX1-bound AP (apurinic/apyrimidinic) 5'-deoxyribose phosphate at the single strand break (SSB) is susceptible to oxidative damage, and can be converted to tetrahydrofuran-like 1,2-dideoxyribose phosphate during base excision repair (BER) (Matsumoto et al. 1994, Klungland and Lindahl 1997).
Homodimers and/or heterodimers of PARP1 and PARP2 bind single strand DNA (ssDNA) ends along with FEN1 (flap endonuclease), forming a ternary complex with POLB (DNA polymerase beta) and simultaneously displacing APEX1 (Prasad et al. 2001, Lavrik et al. 2001, Cistulli et al. 2004). While PARP2 is much less catalytically active than PARP1 in DNA damage-induced poly(ADP-ribosyl) (PAR) synthesis (Shieh et al. 1998, Ame et al. 1999, Fisher et al. 2007), the functional redundancy between PARP1 and PARP2 is probably important. Knockout of both PARP1 and PARP2 homologs is embryonic lethal in mice, while knockout of individual PARPs is not (Menissier de Murcia et al. 2003).
DNA polymerase beta (POLB) catalyzes DNA strand displacement synthesis. In this process, 2-10 nucleotides (dNMPs) are incorporated at the 3' end of the single strand break (SSB). Simultaneously, the other broken DNA strand, which contains a 5' oxidatively-damaged AP dideoxyribose phosphate residue (5'ddRP), is displaced as a flap structure. POLB-mediated DNA strand displacement synthesis is facilitated by PARP1 and/or PARP2 dimers, which bind the single strand DNA (ssDNA) ends and FEN1 (flap endonuclease) (Klungland and Lindahl 1997, Prasad et al. 2001, Lavrik et al. 2001, Liu et al. 2005).
PARP1 or PARP2 homodimers or heterodimers, bound to single strand DNA (ssDNA), POLB and FEN1 at the single strand break (SSB), undergo progressive auto-PARylation causing PARP1/PARP2 to become poly(ADP-ribosyl)ated (Satoh et al. 1994, Prasad et al. 2001).
Auto-PARylated (poly(ADP-ribosylated)) PARP1 or PARP2 homodimers and heterodimers dissociate from DNA at single strand breaks (SSBs). The dissociation of PARP1 and/or PARP2 is necessary for completion of the long patch base excision repair (BER). In the presence of PARP inhibitors, PARP1 and/or PARP2 cannot auto-PARylate and remain bound to SSBs. This leads to persistence of SSBs, and generation of double strand breaks (DSBs) during DNA replication (Creissen and Shall 1982, Sukhanova et al. 2004, Sukhanova et al. 2005, Pachkowski et al. 2009, Heacock et al. 2010, Strom et al. 2011).
DNA ligase I (LIG1) binds DNA polymerase beta (POLB) at the long-patch base excision repair (BER) site. LIG1 and POLB interact through their N-terminal domains (Prasad et al. 1996, Dimitriadis et al. 1998, Tomkinson et al. 2001, Ranalli et al. 2002, Balakrishnan et al. 2009).
POLB-bound FEN1 (flap endonuclease) cleaves the displaced DNA strand (flap structure), which contains the damaged AP residue that could not be excised by POLB (DNA polymerase beta) (Klungland and Lindahl 1997, Prasad et al. 2001, Liu et al. 2005).
LIG1 (DNA ligase I), recruited to the long-patch base excision repair site through its interaction with POLB, ligates the 3' end of the single strand break (SSB), containing the newly synthesized multiple nucleotide repair patch, with the FEN1-processed 5' end of the SSB, thus completing the base excision repair (Prigent et al. 1994, Tomkinson et al. 2001, Ranalli et al. 2002, Balakrishnan et al. 2009).
LIG1 (DNA ligase 1) is recruited to the long-patch base excision repair site through its interaction with APEX1, PCNA and RFC. LIG1 ligates the 3' end of the single strand break (SSB), containing the newly synthesized multiple nucleotide repair patch, with the FEN1-processed 5' end of the SSB, thus completing the base excision repair (Klungland and Lindahl 1997, Tomkinson et al. 2001, Ranalli et al. 2002a). The catalytic activity of LIG1 is stimulated by the presence of PCNA-bound RPA (Ranalli et al. 2002b)
After the PCNA-dependent long patch base excision (BER) is completed, PCNA, APEX1 and LIG1 dissociate from repaired DNA (Klungland and Lindahl 1997, Ranalli et al. 2002a, Ranalli et al. 2002b).
PARG acts as a poly(ADP-ribosyl)glycohydrolase (PAR glycohydrolase) that reverses auto(ADP-ribosyl)ation of PARP1 and/or PARP2 (Kim et al. 2004). PARG activity is required for the turnover of PARP1 and/or PARP2, which allows for the rapid completion of the single strand break (SSB) repair (Fisher et al. 2007). PARG may be recruited to DNA damage site through PCNA binding (Mortusewicz et al. 2011).
After POLB (DNA polymerase beta) fills a single nucleotide gap created by the APEX1 and POLB-mediated excision of the apurinic/apyrimidinic (AP) site in the damaged DNA strand, LIG3 (DNA ligase 3), recruited to POLB-bound AP site by XRCC1, ligates the two DNA strand fragments, thus completing the base excision repair (Kubota et al. 1996).
POLB (DNA polymerase beta) mediates DNA synthesis that fills the gap left after excision of the abasic sugar-phosphate residue, using the undamaged strand as a template (Kubota et al. 1996).
Important cellular processes such as DNA repair, cellular differentiation, and carcinogenesis are regulated by poly(ADP-ribosyl)ation. Previously, only the nuclear protein poly(ADP-ribose) glycohydrolase (PARG) has been identified to hydrolyse poly(ADP-ribose). Poly(ADP-ribose) glycohydrolase ARH3 (ADPRHL2) is a mitochondrial matrix protein (Niere et al. 2008) structurally unrelated to PARG but possessing PARG activity (Oka et al. 2006). ADPRHL2 is able to hydrolyse poly(ADP-ribose) in mitochondria (Niere et al. 2012).
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