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Review
. 2018 Aug 14;19(8):2389.
doi: 10.3390/ijms19082389.

Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

Md Akram Hossain  1 , Yunfeng Lin  2 , Shan Yan  3
Affiliations
Review

Single-Strand Break End Resection in Genome Integrity: Mechanism and Regulation by APE2

Md Akram Hossain et al. Int J Mol Sci. .

Abstract

DNA single-strand breaks (SSBs) occur more than 10,000 times per mammalian cell each day, representing the most common type of DNA damage. Unrepaired SSBs compromise DNA replication and transcription programs, leading to genome instability. Unrepaired SSBs are associated with diseases such as cancer and neurodegenerative disorders. Although canonical SSB repair pathway is activated to repair most SSBs, it remains unclear whether and how unrepaired SSBs are sensed and signaled. In this review, we propose a new concept of SSB end resection for genome integrity. We propose a four-step mechanism of SSB end resection: SSB end sensing and processing, as well as initiation, continuation, and termination of SSB end resection. We also compare different mechanisms of SSB end resection and DSB end resection in DNA repair and DNA damage response (DDR) pathways. We further discuss how SSB end resection contributes to SSB signaling and repair. We focus on the mechanism and regulation by APE2 in SSB end resection in genome integrity. Finally, we identify areas of future study that may help us gain further mechanistic insight into the process of SSB end resection. Overall, this review provides the first comprehensive perspective on SSB end resection in genome integrity.

Keywords: APE2; ATR-Chk1 DDR pathway; Genome integrity; SSB end resection; SSB repair; SSB signaling.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Generation and role of single-strand break (SSB) in genome integrity. SSBs may be derived from DNA sugar or base damage, defective DNA repair, and abortive Top1 activity, and are localized in nucleus and mitochondria. Unrepaired SSBs result in DNA replication stress, transcription stalling, and excessive PARP (Poly ADP-ribose polymerase) activation, leading to genome instability and human diseases such as cancer, heart failure, and neurodegenerative disorders.
Figure 2
Figure 2
Proposed four steps of 3′–5′ SSB end resection: End sensing and processing, initiation, continuation, and termination of SSB end resection.
Figure 3
Figure 3
SSB end resection and DSB end resection. Left panel shows molecular details of 3′–5′ SSB end resection. Following initiation of 3′–5′ SSB end resection via an unknown mechanism, APE2 is recruited and activated by PCNA interaction and ssDNA association. The 3′–5′ SSB end resection is continued by APE2’s 3′–5′ exonuclease activity to generate ssDNA (~18–26 nt) and terminated by an unknown mechanism. The right panel shows molecular details of 5′–3′ DSB end resection. DSB end is recognized by MRN complex and nicked by CtIP-mediated Mre11’s endonuclease activity, followed by bidirectional end resection through 3′–5′ exonuclease activity of the MRN complex and 5′–3′ exonuclease activity of EXO1 (Exonuclease 1). The 5′–3′ DSB end resection is continued by DNA2 to generate a longer stretch of ssDNA (~800 nt).
Figure 4
Figure 4
SSB signaling. Left panel demonstrates replication-independent SSB signaling. Following initiation of SSB end resection, APE2 is recruited and activated by PCNA interaction and ssDNA association. SSB end is resected by APE2 in the 3′–5′ direction to generate ssDNA for RPA recruitment and assembly of ATR DDR protein complex including ATR, ATRIP, TopBP1, and the 9-1-1 complex. Activated ATR phosphorylates Chk1 and RPA32. Right panel shows replication-dependent SSB signaling. When replication fork (rightward or leftward) meets SSB site, one-end DSB and new SSB are generated. The replication-derived SSB may proceed with 3′–5′ SSB end resection and subsequent ATR DDR pathway. The one-end DSB triggers MRN complex recruitment and ATM DDR activation including γ–H2AX and Chk2 phosphorylation.
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