Replication fork stability confers chemoresistance in BRCA-deficient cells

Chaudhuri, Arnab Ray; Callén, Elsa; Ding, Xia; Gogola, Ewa; Duarte, Alexandra A.; Lee, Jieun; Wong, Nancy; Lafarga, Vanessa; Calvo, Jennifer A.; Panzarino, Nicholas J.; John, Sam; Day, Amanda; Crespo, Anna Vidal; Shen, Binghui; Starnes, Linda M.; Ruiter, Julian R. de; Daniel, J.; Konstantinopoulos, Panagiotis A.; Chen, David; Cantor, Sharon B.; Fernández-Capetillo, Óscar; Ge, Kai; Jonkers, Jos; Rottenberg, Sven; Sharan, Shyam K.; Nussenzweig, André

doi:10.1038/nature18325

Cited by 767 publications

(962 citation statements)

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“…In particular, the nucleosome-remodeling factor chromodomain helicase DNA-binding protein 4 (CHD4) was recently shown to promote resistance to replicative stress in BRCA1/2-deficient cells (Guillemette et al 2015, Chaudhuri et al 2016. Thus, the latter discovery provided insight into the mechanism by which factors accumulate at stalled replication forks impact its processing.…”

Section: Brca2 Partners Contribute To Replication Fork Protectionmentioning

confidence: 95%

“…Aside from these functions, this multifaceted protein is involved in numerous other biological processes that impact genome stability, including chromosome segregation during mitosis and cell cycle progression (addressed in Lee 2014). Indeed, aneuploidy is a common feature of BRCA2-deficient cells and this phenomenon is linked to BRCA2 functions in the regulation of centrosome duplication (Schlacher et al 2012, Guillemette et al 2015, Chaudhuri et al 2016, Kais et al 2016, Michl et al 2016, cytokinesis (Daniels et al 2004, Mondal et al 2012 and spindle assembly checkpoint during M phase . Future investigation will be vital to understand how the integration of all BRCA2 functions preserves genome integrity.…”

Section: Discussionmentioning

confidence: 99%

“…Deletion of PARP1, PTIP and CHD4 as well as FANCD2 overexpression provide increased resistance to replication stress in BRCA1/2-deficient cells (Schlacher et al 2012, Guillemette et al 2015, Chaudhuri et al 2016, Kais et al 2016, Michl et al 2016. Although the exact mechanisms by which these proteins participate in the stabilization of stalled replication forks remain elusive, these observations provide a rational to target these factors in the case of relapse/resistance to current therapies.…”

Section: Novel Therapeutic Approachesmentioning

confidence: 99%

“…Interestingly, recent findings in BRCA1/2-deficient cells revealed that resistance to PARPi can occur in an HR-independent manner by acquiring mutations that rescue replication fork stability (Chaudhuri et al 2016, Kais et al 2016, Michl et al 2016. Deletion of PARP1, PTIP and CHD4 as well as FANCD2 overexpression provide increased resistance to replication stress in BRCA1/2-deficient cells (Schlacher et al 2012, Guillemette et al 2015, Chaudhuri et al 2016, Kais et al 2016, Michl et al 2016.…”

Section: Novel Therapeutic Approachesmentioning

confidence: 99%

“…Two key nucleases, the meiotic recombination 11 (MRE11) and DNA2, are thought to drive this step (Costanzo et al 2001, Trenz et al 2006, Hashimoto et al 2010, Thangavel et al 2015; however, the mechanism(s) by which these nucleases recognize and process stalled forks remain unclear. Recent studies suggest that poly (ADP-ribose) polymerase 1 (PARP1) and the histone methyltransferase complex PTIP/mixedlineage leukemia protein 3 et 4 (MLL3/4) promote the recruitment of MRE11 to stalled forks (Bryant et al 2009, Ying et al 2012, Chaudhuri et al 2016. On the other hand, DNA2 acts together with the Werner syndrome ATP-dependent helicase (WRN) at reversed replication forks (Thangavel et al 2015).…”

Section: Brca2 Protects Stalled Replication Forks From Nucleolytic Dementioning

confidence: 99%

See 4 more Smart Citations

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Maintaining genomic integrity is essential to preserve normal cellular physiology and to prevent the emergence of several human pathologies including cancer. The breast cancer susceptibility gene 2 (BRCA2, also known as the Fanconi anemia (FA) complementation group D1 (FANCD1)) is a potent tumor suppressor that has been extensively studied in DNA double-stranded break (DSB) repair by homologous recombination (HR). However, BRCA2 participates in numerous other processes central to maintaining genome stability, including DNA replication, telomere homeostasis and cell cycle progression. Consequently, inherited mutations in BRCA2 are associated with an increased risk of breast, ovarian and pancreatic cancers. Furthermore, bi-allelic mutations in BRCA2 are linked to FA, a rare chromosome instability syndrome characterized by aplastic anemia in children as well as susceptibility to leukemia and cancer. Here, we discuss the recent developments underlying the functions of BRCA2 in the maintenance of genomic integrity. The current model places BRCA2 as a central regulator of genome stability by repairing DSBs and limiting replication stress. These findings have direct implications for the development of novel anticancer therapeutic approaches.

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Section: Brca2 Partners Contribute To Replication Fork Protectionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Section: Novel Therapeutic Approachesmentioning

confidence: 99%

Section: Novel Therapeutic Approachesmentioning

confidence: 99%

Section: Brca2 Protects Stalled Replication Forks From Nucleolytic Dementioning

confidence: 99%

See 3 more Smart Citations

BRCA2 functions: from DNA repair to replication fork stabilization

Fradet-Turcotte¹,

Sitz²,

Grapton³

et al. 2016

Endocrine-Related Cancer

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Small‐molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research

Chheda

Spies

2021

Burger's Medicinal Chemistry and Drug Discovery

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A ubiquitous aspect of cellular life is the need to repair the many deleterious DNA lesions that arise due to environmental damage and as byproducts of normal cellular metabolism. The same DNA repair processes, which are critical for life, are also employed by cancer cells in their resistance to radiation and DNA‐damaging therapies. Inhibition of DNA repair or entrapment of the toxic DNA repair intermediates with the help of small molecules has both potential therapeutic and research utility. Although many proteins that maintain genome integrity and repair DNA damage appear to be attractive targets, they lack well‐defined small‐molecule binding determinants and clear structure–activity relationships. This article summarizes a number of studies that have led to the identification of small‐molecule drug lead compounds, which may also be useful in dissecting complex DNA repair networks. Systems that are particularly noteworthy are inhibition of PARP1, as it is a paradigm case for achieving successful clinical applications, and the emerging targets RAD51 recombinase, RAD52 DNA repair protein, MRE11 nuclease, and WRN DNA helicase.

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Moonlighting at replication forks – a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51

et al. 2017

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Edited by Wilhelm JustCoordination between DNA replication and DNA repair ensures maintenance of genome integrity, which is lost in cancer cells. Emerging evidence has linked homologous recombination (HR) proteins RAD51, BRCA1 and BRCA2 to the stability of nascent DNA. This function appears to be distinct from double-strand break (DSB) repair and is in part due to the prevention of MRE11-mediated degradation of nascent DNA at stalled forks. The role of RAD51 in fork protection resembles the activity described for its prokaryotic orthologue RecA, which prevents nuclease-mediated degradation of DNA and promotes replication fork restart in cells challenged by DNA-damaging agents. Here, we examine the mechanistic aspects of HR-mediated fork protection, addressing the crosstalk between HR and replication proteins.Keywords: DNA recombination; DNA replication; genome stability BRCA1, BRCA2, RAD51 and the RAD51 paralogs family, which consists of five proteins (RAD51B, RAD51C, RAD51D, XRCC2 and XRCC3) in mammalian cells, are required to repair DNA damage by homologous recombination (HR). Mutations in most of these genes predispose to cancer, indicating an important role of DNA damage repair in preventing cell transformation. Intriguingly, complete loss of function of most of HR proteins is incompatible with life in vertebrate organisms [1,2,3]. These features together with their ability to form foci in unperturbed and challenged S-phase nuclei indicate a role for HR proteins in chromosomal DNA replication even in unchallenged conditions [4,5].The mechanisms underlying the function of DNA repair proteins in unchallenged chromosomal DNA replication are poorly understood. This is in part due to the fact that many of the genes involved in DNA metabolism are essential for cell viability, which complicate their study, especially in higher eukaryotes [1,2,3]. The reasons why HR genes are essential for cell viability in higher eukaryotes are unclear. One explanation might be that they have a specific and direct role in the replication of complex eukaryotic genomes. Alternatively, complex genomes might be more vulnerable to spontaneous DNA damage, which might irreversibly halt replication progression inducing chromosomes breakage. HR factors might be therefore required to repair the damage and to complete whole genome duplication. Here we review the links between HR proteins and the DNA replication machinery, some of which appear to be conserved between prokaryotes and eukaryotes.

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Replication fork stability confers chemoresistance in BRCA-deficient cells

Cited by 767 publications

References 44 publications

BRCA2 functions: from DNA repair to replication fork stabilization

BRCA2 functions: from DNA repair to replication fork stabilization

Small‐molecule Effectors of DNA Repair Proteins: Applications for Development of Cancer Therapeutics and Research

Moonlighting at replication forks – a new life for homologous recombination proteins BRCA1, BRCA2 and RAD51

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