Essential Roles for Polymerase θ-Mediated End Joining in the Repair of Chromosome Breaks

David W. Wyatt, Wanjuan Feng, Michael P. Conlin, Matthew J. Yousefzadeh, Steven A. Roberts, Piotr Mieczkowski, Richard D. Wood, Gaorav P. Gupta, Dale A. Ramsden

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

DNA polymerase theta (Pol θ)-mediated end joining (TMEJ) has been implicated in the repair of chromosome breaks, but its cellular mechanism and role relative to canonical repair pathways are poorly understood. We show that it accounts for most repairs associated with microhomologies and is made efficient by coupling a microhomology search to removal of non-homologous tails and microhomology-primed synthesis across broken ends. In contrast to non-homologous end joining (NHEJ), TMEJ efficiently repairs end structures expected after aborted homology-directed repair (5′ to 3′ resected ends) or replication fork collapse. It typically does not compete with canonical repair pathways but, in NHEJ-deficient cells, is engaged more frequently and protects against translocation. Cell viability is also severely impaired upon combined deficiency in Pol θ and a factor that antagonizes end resection (Ku or 53BP1). TMEJ thus helps to sustain cell viability and genome stability by rescuing chromosome break repair when resection is misregulated or NHEJ is compromised.

Original languageEnglish (US)
Pages (from-to)662-673
Number of pages12
JournalMolecular Cell
Volume63
Issue number4
DOIs
StatePublished - Aug 18 2016

Bibliographical note

Funding Information:
Our studies were supported by NCI Grant CA097096 (to D.A.R.), AHA Grant 14PRE20380258 (to D.W.W.), RP130297 and RP150102 from the Cancer Prevention and Research Institute of Texas and a Grady F. Saunders Research Professorship (to R.D.W.), T32 CA09480 (to M.J.Y.), DOD Grant BC141727 and NIEHS Grant R00ES02633 (to S.A.R.), and the Burroughs Welcome Fund Career Award for Medical Scientists (to G.P.G.). We thank Luis Blanco for the gift of Polm −/− Pol −/− MEFs and Juan Carvajal-Garcia and George W. Small for methods development.

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