Genome Protection by the 9-1-1 Complex Subunit HUS1 Requires Clamp Formation, DNA Contacts, and ATR Signaling-independent Effector Functions

Lim, Pei Xin; Patel, Darshil; Poisson, Kelsey E.; Basuita, Manpreet; Tsai, Charlton; Lyndaker, Amy M.; Hwang, Bor-Jang; Lu, A-Lien; Weiss, Robert S.

doi:10.1074/jbc.m114.630640

Cited by 15 publications

(23 citation statements)

References 49 publications

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“…Indeed, our recent studies have identified a requirement for the 9-1-1 complex in protecting stalled RFs against MRE11-dependent nascent strand degradation following replication stress (unpublished results from Weiss lab). Although 9-1-1 has multiple, separable functions in the DDR (59), it is ATR activation by 9-1-1 that is particularly important for fork protection, a finding that is consistent with prior studies linking ATR to replication fork stability (13, 60–62). A challenge for the field moving forward is to determine how these new players, including ABRO1, BOD1L, and 9-1-1, fit into the existing landscape of RF protection and repair.…”

Section: Additional Ddr Factors Besides Canonical Hr/fa Proteins Alsosupporting

confidence: 84%

A tough row to hoe: when replication forks encounter DNA damage

Patel

Weiss

2018

Biochemical Society Transactions

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Eukaryotic cells continuously experience DNA damage that can perturb key molecular processes like DNA replication. DNA replication forks that encounter DNA lesions typically slow and may stall, which can lead to highly detrimental fork collapse if appropriate protective measures are not executed. Stabilization and protection of stalled replication forks ensures the possibility of effective fork restart and prevents genomic instability. Recent efforts from multiple laboratories have highlighted several proteins involved in replication fork remodeling and DNA damage response pathways as key regulators of fork stability. Homologous recombination factors such as RAD51, BRCA1, and BRCA2, along with components of the Fanconi Anemia pathway, are now known to be crucial for stabilizing stalled replication forks and preventing nascent strand degradation. Several checkpoint proteins have additionally been implicated in fork protection. Ongoing work in this area continues to shed light on a sophisticated molecular pathway that balances the action of DNA resection and fork protection to maintain genomic integrity, with important implications for the fate of both normal and malignant cells following replication stress.

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Section: Additional Ddr Factors Besides Canonical Hr/fa Proteins Alsosupporting

confidence: 84%

A tough row to hoe: when replication forks encounter DNA damage

Patel

Weiss

2018

Biochemical Society Transactions

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“…The 9-1-1 checkpoint clamp promotes HR and facilitates repair of various types of replication lesions, including those triggered by ICLs, bulky adducts, and ssDNA gaps ( 32 , 33 ). Because these features are overlapping to what we uncovered here for ddx11 , we next analyzed the functional interaction between DDX11 and 9-1-1.…”

Section: Resultsmentioning

confidence: 99%

Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites

Abe

Ooka

Kawasumi

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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SignificanceWarsaw breakage syndrome, a developmental disorder caused by mutations in the conserved DDX11/ChlR1 DNA helicase, shows features of genome instability partly overlapping with those of Fanconi anemia (FA). Here, using avian cellular models of DDX11 deficiency, we find that DDX11 functions as backup to the FA pathway and facilitates, jointly with the checkpoint clamp 9-1-1, a homologous recombination pathway of DNA bulky-lesion repair that does not affect replication fork speed and stalled fork stability. DDX11 also promotes diversification of the immunoglobulin-variable gene locus by facilitating hypermutation and gene conversion at programmed abasic sites that constitute endogenous replication blocks. The results suggest commonality between postreplicative gap filling and replication through abasic sites and pinpoint DDX11 as a critical player in both these processes.

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“…However, the signaling events that direct these activities, the factors that dictate chromosome ploidy variation, and the dynamics of genome maintenance in this organism are still not well understood. The Rad9–Rad1–Hus1 (9–1–1) complex is a ring-shaped trimeric clamp that is loaded onto DNA in response to replication stress, serving as a scaffold for the association of downstream factors that can lead to cell-cycle arrest until single strand DNA resulting from replication stress is resolved (12,13). In addition, the 9–1–1 complex is involved with DNA damage repair and telomere maintenance (14–16).…”

Section: Introductionmentioning

confidence: 99%

Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9–1–1 complex in the maintenance of the plastic genome ofLeishmania

Damasceno

Obonaga

Silva

et al. 2018

Nucleic Acids Research

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Leishmania species are protozoan parasites whose remarkably plastic genome limits the establishment of effective genetic manipulation and leishmaniasis treatment. The strategies used by Leishmania to maintain its genome while allowing variability are not fully understood. Here, we used DiCre-mediated conditional gene deletion to show that HUS1, a component of the 9–1–1 (RAD9-RAD1-HUS1) complex, is essential and is required for a G2/M checkpoint. By analyzing genome-wide instability in HUS1 ablated cells, HUS1 is shown to have a conserved role, by which it preserves genome stability and also a divergent role, by which it promotes genome variability. These roles of HUS1 are related to distinct patterns of formation and resolution of single-stranded DNA and γH2A, throughout the cell cycle. Our findings suggest that Leishmania 9–1–1 subunits have evolved to co-opt canonical genomic maintenance and genomic variation functions. Hence, this study reveals a pivotal function of HUS1 in balancing genome stability and transmission in Leishmania. These findings may be relevant to understanding the evolution of genome maintenance and plasticity in other pathogens and eukaryotes.

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Genome Protection by the 9-1-1 Complex Subunit HUS1 Requires Clamp Formation, DNA Contacts, and ATR Signaling-independent Effector Functions

Cited by 15 publications

References 49 publications

A tough row to hoe: when replication forks encounter DNA damage

A tough row to hoe: when replication forks encounter DNA damage

Warsaw breakage syndrome DDX11 helicase acts jointly with RAD17 in the repair of bulky lesions and replication through abasic sites

Conditional genome engineering reveals canonical and divergent roles for the Hus1 component of the 9–1–1 complex in the maintenance of the plastic genome ofLeishmania

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