Resolution of Abasic Sites (AP sites)

Stable Identifier
Homo sapiens
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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).
Literature References
PubMed ID Title Journal Year
15871698 The human checkpoint sensor and alternative DNA clamp Rad9-Rad1-Hus1 modulates the activity of DNA ligase I, a component of the long-patch base excision repair machinery

Toueille, M, Hübscher, U, Smirnova, E, Markkanen, E

Biochem. J. 2005
11601988 Interaction of human AP endonuclease 1 with flap endonuclease 1 and proliferating cell nuclear antigen involved in long-patch base excision repair

Dianova, II, Bohr, VA, Dianov, GL

Biochemistry 2001
8978692 Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 protein.

Lindahl, T, Kubota, Y, Nash, RA, Klungland, A, Schär, P, Barnes, DE

EMBO J 1997
9207062 Interaction of human apurinic endonuclease and DNA polymerase beta in the base excision repair pathway.

Wilson, DM, Wong, D, Bennett, RA, Demple, B

Proc Natl Acad Sci U S A 1997
9804798 Dynamics of the interaction of human apurinic endonuclease (Ape1) with its substrate and product.

Bennett, RA, Demple, B, Masuda, Y

J Biol Chem 1998
15260972 AP endonuclease-independent DNA base excision repair in human cells

Karimi-Busheri, F, Weinfeld, M, Mitra, S, Wiederhold, L, Izumi, T, Hazra, TK, Kedar, P, Wilson, SH, Leppard, JB, Prasad, R, Rasouli-Nia, A, Tomkinson, AE

Mol. Cell 2004
9214649 Second pathway for completion of human DNA base excision-repair: reconstitution with purified proteins and requirement for DNase IV (FEN1).

Lindahl, T, Klungland, A

EMBO J 1997
15556996 The human Rad9-Rad1-Hus1 checkpoint complex stimulates flap endonuclease 1

Fanning, E, Lindsey-Boltz, LA, Rossi, ML, Brandt, P, Sancar, A, Podust, V, Wang, W, Bambara, RA

Proc Natl Acad Sci U S A 2004
19329425 Long patch base excision repair proceeds via coordinated stimulation of the multienzyme DNA repair complex

Lindsey-Boltz, LA, Sancar, A, Brandt, PD, Bambara, RA, Balakrishnan, L

J. Biol. Chem. 2009
7608159 Incision activity of human apurinic endonuclease (Ape) at abasic site analogs in DNA

Wilson, DM, Grollman, AP, Demple, B, Takeshita, M

J. Biol. Chem. 1995
16982218 NEIL2-initiated, APE-independent repair of oxidized bases in DNA: Evidence for a repair complex in human cells

Karimi-Busheri, F, Wang, H, Weinfeld, M, Mitra, S, Hazra, TK, Kedar, P, Wilson, SH, Leppard, JB, Prasad, R, Boldogh, I, Tomkinson, AE, Wiederhold, L, Das, A

DNA Repair (Amst.) 2006
11440997 DNA polymerase beta -mediated long patch base excision repair. Poly(ADP-ribose)polymerase-1 stimulates strand displacement DNA synthesis

Vande Berg, BJ, Wilson, SH, Kim, SJ, Kedar, P, Yang, XP, Lavrik, OI, Prasad, R

J. Biol. Chem. 2001
17395641 The human checkpoint sensor Rad9-Rad1-Hus1 interacts with and stimulates NEIL1 glycosylase

Theriot, CA, Bai, H, Mitra, S, Shi, G, Hazra, TK, Guan, X, Lu, AL

Nucleic Acids Res. 2007
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