Reactome | Resolution of AP sites via the multiple-nucleotide patch replacement pathway

Resolution of AP sites via the multiple-nucleotide patch replacement pathway

Stable Identifier

R-HSA-110373

Type

Pathway

Species

Homo sapiens

Compartment

nucleoplasm

ReviewStatus

5/5

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Resolution of AP sites via the multiple-nucleotide patch replacement pathway

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While the single nucleotide replacement pathway appears to facilitate the repair of most damaged bases, an alternative BER pathway is evoked when the structure of the 5'-terminal sugar phosphate is such that it cannot be cleaved through the AP lyase activity of DNA polymerase beta (POLB). Under these circumstances, a short stretch of residues containing the abasic site is excised and replaced (Dianov et al., 1999). Following DNA glycosylase-mediated cleavage of the damaged base, the endonuclease APEX1 is recruited to the site of damage where it cleaves the 5' side of the abasic deoxyribose residue, as in the single nucleotide replacement pathway. However, POLB then synthesizes the first replacement residue without prior cleavage of the 5'-terminal sugar phosphate, hence displacing this entity. Long-patch BER can be completed by continued 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 the 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). In both POLB-dependent and PCNA-dependent DNA displacement synthesis, the displaced DNA strand containing the abasic sugar phosphate creates a flap structure that is recognized and cleaved by the flap endonuclease FEN1. The replacement residues added by POLB or POLD/POLE are then ligated by the DNA ligase I (LIG1) (Klungland and Lindahl, 1997; Matsumoto et al., 1999).

Literature References

PubMed ID	Title	Journal	Year
10559261	Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/apyrimidinic sites with purified human proteins. Tomkinson, AE, Hurwitz, J, Matsumoto, Y, Levin, DS, Park, MS, Kim, K, Gary, R	J Biol Chem	1999
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
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
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
10583946	Quality control by DNA repair Lindahl, T, Wood, RD	Science	1999
10460157	Replication protein A stimulates proliferating cell nuclear antigen-dependent repair of abasic sites in DNA by human cell extracts. Bohr, VA, Kenny, MK, Dianov, GL, Jensen, BR	Biochemistry	1999