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

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.

Genomic alterations and abnormal expression of APE2 in multiple cancers

“…Although the exact underlying mechanism remains unknown, this report suggests that APE2 may contribute to different DNA repair pathways other than BRCA1-and BRCA2-mediated DSB repair. Consistent with this, our series of studies using Xenopus egg extract system suggest that APE2 plays a direct role in SSB repair via the 3′-5′ SSB end resection 11,26,43 . Of note, gene expression of APE2 and APE1 has been found up-regulated in multiple myeloma (MM) patients and MM cells, which may lead to dysregulation of HR via regulating Rad51 expression 32 .…”

“…AP endonuclease 1 (APE1, also known as APEX1, Apn1, or Ref-1) and AP endonuclease 2 (APE2, also known as APEX2 or Apn2) have been implicated in many regulatory mechanisms in the maintenance of genome stability, especially in BER pathway 8,25,26 . In addition to its transcriptional activity of redox regulation, APE1 is the main AP endonuclease with high endonuclease activity yet weak exonuclease activity to promote BER 8,25,27 .…”

DNA fragmentation of human spermatozoa: Simple assessment of single‐ and double‐strand DNA breaks and their respective dynamic behavioral response

“…This may be particularly the case when SSBs are massively present within the same sperm nucleus so that DNA repair by the oocyte may be compromised. The higher the incidence of SSBs, the higher the chance of mis‐repair or persistence of the breakage leading to DSBs during DNA replication 48‐50 . For example, this phenomenon has previously been demonstrated after cell treatment with inhibitors of topoisomerase I 51,52 .…”

Therapeutic Strategies and Biomarkers to Modulate PARP Activity for Targeted Cancer Therapy

“…The PARylated proteins then recruit and retain critical processing factors to the site of the lesion to facilitate the efficient repair of the SSB ( Figure 1A) [7]. In the absence of PARP1, unrepaired SSBs are converted to double-stranded breaks (DSBs) during replication or the S-phase of the cell cycle [8]. Double-stranded DNA breaks are one of the most lethal forms of DNA damage induced by exogenous DNA damaging agents (e.g., ionizing radiation (IR) and chemotherapeutic agents) or endogenous replicative stress in fast proliferating cancer cells.…”