Skip Navigation

Publication Detail

Title: HMCES Maintains Replication Fork Progression and Prevents Double-Strand Breaks in Response to APOBEC Deamination and Abasic Site Formation.

Authors: Mehta, Kavi P M; Lovejoy, Courtney A; Zhao, Runxiang; Heintzman, Darren R; Cortez, David

Published In Cell Rep, (2020 06 02)

Abstract: 5-Hydroxymethylcytosine (5hmC) binding, ES-cell-specific (HMCES) crosslinks to apurinic or apyrimidinic (AP, abasic) sites in single-strand DNA (ssDNA). To determine whether HMCES responds to the ssDNA abasic site in cells, we exploited the activity of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3A (APOBEC3A). APOBEC3A preferentially deaminates cytosines to uracils in ssDNA, which are then converted to abasic sites by uracil DNA glycosylase. We find that HMCES-deficient cells are hypersensitive to nuclear APOBEC3A localization. HMCES relocalizes to chromatin in response to nuclear APOBEC3A and protects abasic sites from processing into double-strand breaks (DSBs). Abasic sites induced by APOBEC3A slow both leading and lagging strand synthesis, and HMCES prevents further slowing of the replication fork by translesion synthesis (TLS) polymerases zeta (Polζ) and kappa (Polκ). Thus, our study provides direct evidence that HMCES responds to ssDNA abasic sites in cells to prevent DNA cleavage and balance the engagement of TLS polymerases.

PubMed ID: 32492421 Exiting the NIEHS site

MeSH Terms: 5-Methylcytosine/analogs & derivatives; 5-Methylcytosine/metabolism; Cell Line; Cell Nucleus/metabolism; Chromatin/metabolism; Cytidine Deaminase/genetics; Cytidine Deaminase/metabolism*; DNA Breaks, Double-Stranded*; DNA Replication; DNA, Single-Stranded/metabolism; DNA-(Apurinic or Apyrimidinic Site) Lyase/antagonists & inhibitors; DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics; DNA-(Apurinic or Apyrimidinic Site) Lyase/metabolism; DNA-Binding Proteins/antagonists & inhibitors; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism*; DNA-Directed DNA Polymerase/chemistry; DNA-Directed DNA Polymerase/genetics; DNA-Directed DNA Polymerase/metabolism; Deamination; Endonucleases/antagonists & inhibitors; Endonucleases/genetics; Endonucleases/metabolism; Humans; Multifunctional Enzymes/antagonists & inhibitors; Multifunctional Enzymes/genetics; Multifunctional Enzymes/metabolism; Proteins/genetics; Proteins/metabolism*; RNA Interference; RNA, Small Interfering/metabolism; Uracil-DNA Glycosidase/metabolism; Uracil/metabolism

Back
to Top