Repair of base damage within break-induced replication intermediates promotes kataegis associated with chromosome rearrangements

Nucleic Acids Research
Rajula ElangoAnna Malkova

Abstract

Break induced replication (BIR) is a double strand break repair pathway that can promote genetic instabilities similar to those observed in cancer. Instead of a replication fork, BIR is driven by a migration bubble where asynchronous synthesis between leading and lagging strands leads to accumulation of single-stranded DNA (ssDNA) that promotes mutation. However, the details of the mechanism of mutagenesis, including the identity of the participating proteins, remain unknown. Using yeast as a model, we demonstrate that mutagenic ssDNA is formed at multiple positions along the BIR track and that Pol ζ is responsible for the majority of both spontaneous and damage-induced base substitutions during BIR. We also report that BIR creates a potent substrate for APOBEC3A (A3A) cytidine deaminase that can promote formation of mutation clusters along the entire track of BIR. Finally, we demonstrate that uracil glycosylase initiates the bypass of DNA damage induced by A3A in the context of BIR without formation of base substitutions, but instead this pathway frequently leads to chromosomal rearrangements. Together, the expression of A3A during BIR in yeast recapitulates the main features of APOBEC-induced kataegis in human cancers, sugges...Continue Reading

References

Mar 23, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Vladimir P PoltoratskyYouri I Pavlov
Dec 21, 2006·International Review of Cytology·Youri I PavlovIgor B Rogozin
Apr 6, 2007·Nature·Catherine E SmithLorraine S Symington
Mar 8, 2008·Science·Thanos D HalazonetisJiri Bartek
Mar 5, 2009·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Amy M Lyndaker, Eric Alani
Feb 25, 2011·PLoS Biology·Angela DeemAnna Malkova
Mar 17, 2011·Cell Cycle·Lauranell H BurchDmitry A Gordenin
May 23, 2012·Cell·Serena Nik-ZainalUNKNOWN Breast Cancer Working Group of the International Cancer Genome Consortium
Jan 16, 2013·Cell Reports·Ludmil B AlexandrovMichael R Stratton
Feb 8, 2013·Nature·Michael B BurnsReuben S Harris
Apr 3, 2013·Proceedings of the National Academy of Sciences of the United States of America·Yotam DrierEytan Domany
Jul 16, 2013·Nature Genetics·Steven A RobertsDmitry A Gordenin
Jul 25, 2013·Cold Spring Harbor Perspectives in Biology·Ranjith P AnandJames E Haber
Jul 31, 2013·Proceedings of the National Academy of Sciences of the United States of America·Roberto A Donnianni, Lorraine S Symington
Aug 16, 2013·Nature·Ludmil B AlexandrovMichael R Stratton
Mar 13, 2014·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Steven A Roberts, Dmitry A Gordenin
Jun 3, 2014·Cell Reports·Cynthia J SakofskyAnna Malkova
Jan 9, 2015·Nature Reviews. Cancer·Steven A Roberts, Dmitry A Gordenin
Jun 5, 2015·Mutation Research. Reviews in Mutation Research·Xin XuWei Xiao
Jun 21, 2015·Cancer Discovery·Charles SwantonReuben S Harris
Aug 5, 2015·Cold Spring Harbor Perspectives in Biology·Wolf-Dietrich Heyer
Dec 4, 2015·Annual Review of Genetics·Kin Chan, Dmitry A Gordenin
Dec 9, 2015·Trends in Cancer·Robert L Dilley, Roger A Greenberg

❮ Previous
Next ❯

Citations

Apr 12, 2020·Proceedings of the National Academy of Sciences of the United States of America·Yang SuiDao-Qiong Zheng
May 1, 2020·Proceedings of the National Academy of Sciences of the United States of America·Hannah L Klein
Apr 16, 2020·Trends in Genetics : TIG·Kez Cleal, Duncan M Baird
May 22, 2020·DNA Repair·Natalie Saini, Dmitry A Gordenin
Apr 8, 2021·Seminars in Cell & Developmental Biology·Rashmi DahiyaPeter Ly
Nov 18, 2020·Trends in Genetics : TIG·Alex V NestaChristine R Beck
Apr 2, 2021·Annual Review of Biochemistry·Z W KocklerA Malkova
Aug 14, 2021·Trends in Cell Biology·Esther A Epum, James E Haber

❮ Previous
Next ❯

Datasets Mentioned

BETA
PRJNA517571

Methods Mentioned

BETA
deamination
PCR
electrophoresis
Illumina sequencing

Software Mentioned

CLC Genomic Workbench
CLC Genomics Workbench

Related Concepts

Related Feeds

Cell Migration

Cell migration is involved in a variety of physiological and pathological processes such as embryonic development, cancer metastasis, blood vessel formation and remoulding, tissue regeneration, immune surveillance and inflammation. Here is the latest research.

Attention Disorders

Attention is involved in all cognitive activities, and attention disorders are reported in patients with various neurological diseases. Here are the latest discoveries pertaining to attention disorders.

Cell Migration in Cancer and Metastasis

Migration of cancer cells into surrounding tissue and the vasculature is an initial step in tumor metastasis. Discover the latest research on cell migration in cancer and metastasis here.