BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks

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

doi:10.1016/j.molcel.2015.06.007

BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	462-77
Number of pages	16
Journal	Molecular Cell
Volume	59
Issue number	3
Early online date	9 Jul 2015
DOIs	https://doi.org/10.1016/j.molcel.2015.06.007
Publication status	Published - 6 Aug 2015

Keywords

Cell Cycle Proteins/genetics
Cell Line
Cell Survival
DNA Damage
DNA Helicases/metabolism
DNA Replication
DNA-Binding Proteins/metabolism
Genome, Human
Genomic Instability
HeLa Cells
Humans
Rad51 Recombinase/genetics
RecQ Helicases/metabolism

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Higgs, M. R., Reynolds, J. J., Winczura, A., Blackford, A. N., Borel, V., Miller, E. S., Zlatanou, A., Nieminuszczy, J., Ryan, E. L., Davies, N. J., Stankovic, T., Boulton, S. J., Niedzwiedz, W., & Stewart, G. S. (2015). BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks. Molecular Cell, 59(3), 462-77. https://doi.org/10.1016/j.molcel.2015.06.007

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title = "BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks",

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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AU - Higgs, Martin R

AU - Reynolds, John J

AU - Winczura, Alicja

AU - Blackford, Andrew N

AU - Borel, Valérie

AU - Miller, Edward S

AU - Zlatanou, Anastasia

AU - Nieminuszczy, Jadwiga

AU - Ryan, Ellis L

AU - Davies, Nicholas J

AU - Stankovic, Tatjana

AU - Boulton, Simon J

AU - Niedzwiedz, Wojciech

AU - Stewart, Grant S

PY - 2015/8/6

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N2 - 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.

AB - 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.

KW - Cell Cycle Proteins/genetics

KW - Cell Line

KW - Cell Survival

KW - DNA Damage

KW - DNA Helicases/metabolism

KW - DNA Replication

KW - DNA-Binding Proteins/metabolism

KW - Genome, Human

KW - Genomic Instability

KW - HeLa Cells

KW - Humans

KW - Rad51 Recombinase/genetics

KW - RecQ Helicases/metabolism

UR - https://www.cell.com/molecular-cell/fulltext/S1097-2765(15)00446-3

U2 - 10.1016/j.molcel.2015.06.007

DO - 10.1016/j.molcel.2015.06.007

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SP - 462

EP - 477

JO - Molecular Cell

JF - Molecular Cell

IS - 3

ER -

BOD1L Is Required to Suppress Deleterious Resection of Stressed Replication Forks

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Keywords

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