BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks

Mol Cell. 2015 Aug 6;59(3):462-77. doi: 10.1016/j.molcel.2015.06.007.

Martin R Higgs ¹, John J Reynolds ¹, Alicja Winczura ², Andrew N Blackford ², Valérie Borel ³, Edward S Miller ¹, Anastasia Zlatanou ¹, Jadwiga Nieminuszczy ², Ellis L Ryan ¹, Nicholas J Davies ¹, Tatjana Stankovic ¹, Simon J Boulton ³, Wojciech Niedzwiedz ², Grant S Stewart ⁴

Affiliations

1 School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK.
2 The Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
3 The Francis Crick Institute, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, UK.
4 School of Cancer Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: [email protected].

PMID: 26166705 DOI: 10.1016/j.molcel.2015.06.007

Abstract

Recognition and repair of damaged replication forks are essential to maintain genome stability and are coordinated by the combined action of the Fanconi anemia and homologous recombination pathways. These pathways are vital to protect stalled replication forks from uncontrolled nucleolytic activity, which otherwise causes irreparable genomic damage. Here, we identify BOD1L as a component of this fork protection pathway, which safeguards genome stability after replication stress. Loss of BOD1L confers exquisite cellular sensitivity to replication stress and uncontrolled resection of damaged replication forks, due to a failure to stabilize RAD51 at these forks. Blocking DNA2-dependent resection, or downregulation of the helicases BLM and FBH1, suppresses both catastrophic fork processing and the accumulation of chromosomal damage in BOD1L-deficient cells. Thus, our work implicates BOD1L as a critical regulator of genome integrity that restrains nucleolytic degradation of damaged replication forks.

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