HMCES Maintains Replication Fork Progression and Prevents Double-Strand Breaks in Response to APOBEC Deamination and Abasic Site Formation
| Autor: | David Cortez, Courtney A. Lovejoy, Kavi P.M. Mehta, Darren R. Heintzman, Runxiang Zhao |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
DNA Replication replication stress DNA repair DNA damage DNA Single-Stranded DNA-Directed DNA Polymerase General Biochemistry Genetics and Molecular Biology Article Cell Line 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cytidine Deaminase abasic site DNA-(Apurinic or Apyrimidinic Site) Lyase Humans AP site DNA Breaks Double-Stranded APOBEC3A RNA Small Interfering Uracil Uracil-DNA Glycosidase lcsh:QH301-705.5 Cell Nucleus APOBEC Proteins HMCES Endonucleases Multifunctional Enzymes Chromatin Cell biology DNA-Binding Proteins 030104 developmental biology lcsh:Biology (General) chemistry Deamination Uracil-DNA glycosylase 5-Methylcytosine RNA Interference Abasic Site Formation 030217 neurology & neurosurgery DNA |
| Zdroj: | Cell reports Cell Reports, Vol 31, Iss 9, Pp-(2020) |
| ISSN: | 2211-1247 |
| Popis: | SUMMARY 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. In Brief Mehta et al. use APOBEC3A to demonstrate that HMCES responds to ssDNA abasic sites in cells and prevents replication fork collapse. APOBEC3A-induced abasic sites slow both leading and lagging strand polymerization, and HMCES engagement prevents further fork slowing because of the action of TLS polymerases zeta (Polζ) and kappa (Polκ). Graphical Abstract |
| Databáze: | OpenAIRE |
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