RAD-ical New Insights into RAD51 Regulation.
Reads0
Chats0
TLDR
The current perspective on the in vivo and in vitro function of the RAD51 paralogs is discussed, and their relationship with cancer in vertebrate models is discussed.Abstract:
The accurate repair of DNA is critical for genome stability and cancer prevention. DNA double-strand breaks are one of the most toxic lesions; however, they can be repaired using homologous recombination. Homologous recombination is a high-fidelity DNA repair pathway that uses a homologous template for repair. One central HR step is RAD51 nucleoprotein filament formation on the single-stranded DNA ends, which is a step required for the homology search and strand invasion steps of HR. RAD51 filament formation is tightly controlled by many positive and negative regulators, which are collectively termed the RAD51 mediators. The RAD51 mediators function to nucleate, elongate, stabilize, and disassemble RAD51 during repair. In model organisms, RAD51 paralogs are RAD51 mediator proteins that structurally resemble RAD51 and promote its HR activity. New functions for the RAD51 paralogs during replication and in RAD51 filament flexibility have recently been uncovered. Mutations in the human RAD51 paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and SWSAP1) are found in a subset of breast and ovarian cancers. Despite their discovery three decades ago, few advances have been made in understanding the function of the human RAD51 paralogs. Here, we discuss the current perspective on the in vivo and in vitro function of the RAD51 paralogs, and their relationship with cancer in vertebrate models.read more
Citations
More filters
Journal ArticleDOI
Computed structures of core eukaryotic protein complexes.
Ian R. Humphreys,Jimin Pei,Minkyung Baek,Aditya Krishnakumar,Ivan Anishchenko,Sergey Ovchinnikov,Jing Zhang,Travis J. Ness,Sudeep Banjade,Saket R. Bagde,Viktoriya G. Stancheva,Xiao-Han Li,Kaixian Liu,Zhi Zheng,Zhi Zheng,Daniel J. Barrero,Upasana Roy,Jochen Kuper,Israel S. Fernández,Barnabas Szakal,Dana Branzei,Josep Rizo,Caroline Kisker,Eric C. Greene,Sue Biggins,Scott Keeney,Scott Keeney,Elizabeth A. Miller,J. Christopher Fromme,Tamara L. Hendrickson,Qian Cong,David Baker +31 more
TL;DR: The structures of many eukaryotic protein complexes are unknown, and there are likely many protein-protein interactions not yet identified as mentioned in this paper, but these structures play critical roles in biology.
Journal ArticleDOI
The Unfolded Protein Response: Detecting and Responding to Fluctuations in the Protein-Folding Capacity of the Endoplasmic Reticulum
TL;DR: Recent developments in the field that have provided new insights into the ER stress-sensing mechanisms used by UPR sensors and the mechanisms by which they integrate various cellular inputs to adjust the folding capacity of the organelle to accommodate to fluctuations in ER protein-folding demands are reviewed.
Journal ArticleDOI
RAD51 Gene Family Structure and Function.
TL;DR: This review focuses on mammalian RAD51 structure and function and highlights the use of model systems to enable mechanistic understanding of RAD51 cellular roles and how misregulation of the RAD51 gene family members contributes to disease and consider new approaches to pharmacologically inhibit RAD51.
Journal ArticleDOI
Role of Rad51 and DNA repair in cancer: A molecular perspective.
Erik Laurini,Domenico Marson,Alice Fermeglia,Suzana Aulic,Maurizio Fermeglia,Sabrina Pricl,Sabrina Pricl +6 more
TL;DR: An overview of the main DNA repair pathways, with special focus on the role played by homologous repair and the RAD51 recombinase protein in the cellular DNA damage response, and a survey of the most promising therapeutic strategies aimed at targeting RAD51 in experimental oncology.
Journal ArticleDOI
Sequential role of RAD51 paralog complexes in replication fork remodeling and restart.
Matteo Berti,Federico Teloni,Sofija Mijic,Sebastian Ursich,Jevgenij Fuchs,Maria Dilia Palumbieri,Jana Krietsch,Jonas A. Schmid,Edwige B. Garcin,Stéphanie Gon,Mauro Modesti,Matthias Altmeyer,Massimo Lopes +12 more
TL;DR: It is proposed that RAD51 paralogs sequentially orchestrate clinically relevant transactions at replication forks, cooperatively promoting fork remodeling and restart, providing insights on the mechanistic role of different complexes of these proteins.
References
More filters
Journal ArticleDOI
Hallmarks of cancer: the next generation.
TL;DR: Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer.
Journal ArticleDOI
The DNA-damage response in human biology and disease
Stephen P. Jackson,Jiri Bartek +1 more
TL;DR: The authors' improving understanding of DNA-damage responses is providing new avenues for disease management, and these responses are biologically significant because they prevent diverse human diseases.
Journal ArticleDOI
Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase
Helen E. Bryant,Nilklas Schultz,Huw D. Thomas,Kayan M. Parker,Dan Flower,Elena Lopez,Suzanne Kyle,Mark Meuth,Nicola J. Curtin,Thomas Helleday,Thomas Helleday +10 more
TL;DR: It is proposed that, in the absence of PARP1, spontaneous single-strand breaks collapse replication forks and trigger homologous recombination for repair and exploited in order to kill BRCA2-deficient tumours by PARP inhibition alone.
Journal ArticleDOI
The DNA Damage Response: Making It Safe to Play with Knives
TL;DR: This review will focus on how the DDR controls DNA repair and the phenotypic consequences of defects in these critical regulatory functions in mammals.
Journal ArticleDOI
Inhibition of Poly(ADP-Ribose) Polymerase in Tumors from BRCA Mutation Carriers
Peter C.C. Fong,D. S. Boss,Timothy A. Yap,Andrew Tutt,Peijun Wu,Marja Mergui-Roelvink,Peter S. Mortimer,Helen Swaisland,Alan Lau,Mark J. O'Connor,Alan Ashworth,James Carmichael,Stan B. Kaye,Jan H.M. Schellens,Jan H.M. Schellens,Johann S. de Bono +15 more
TL;DR: Olaparib has few of the adverse effects of conventional chemotherapy, inhibits PARP, and has antitumor activity in cancer associated with the BRCA1 or BRCa2 mutation.
Related Papers (5)
RPA and RAD51: fork reversal, fork protection, and genome stability
Kamakoti P. Bhat,David Cortez +1 more