title: The RASSF1A tumor suppressor regulates XPA-mediated DNA repair.
abstract: RASSF1A may be the most frequently inactivated tumor suppressor identified in human cancer so far. It is a proapoptotic Ras effector and plays an important role in the apoptotic DNA damage response (DDR). We now show that in addition to DDR regulation, RASSF1A also plays a key role in the DNA repair process itself. We show that RASSF1A forms a DNA damage-regulated complex with the key DNA repair protein xeroderma pigmentosum A (XPA). XPA requires RASSF1A to exert full repair activity, and RASSF1A-deficient cells exhibit an impaired ability to repair DNA. Moreover, a cancer-associated RASSF1A single-nucleotide polymorphism (SNP) variant exhibits differential XPA binding and inhibits DNA repair. The interaction of XPA with other components of the repair complex, such as replication protein A (RPA), is controlled in part by a dynamic acetylation/deacetylation cycle. We found that RASSF1A and its SNP variant differentially regulate XPA protein acetylation, and the SNP variant hyperstabilizes the XPA-RPA70 complex. Thus, we identify two novel functions for RASSF1A in the control of DNA repair and protein acetylation. As RASSF1A modulates both apoptotic DDR and DNA repair, it may play an important and unanticipated role in coordinating the balance between repair and death after DNA damage.
authors.affiliation: Department of Medicine, J. G. Brown Cancer Center, Molecular Targets Program, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Howard
authors.initials: H
authors.lastname: Donninger
authors.affiliation: Department of Medicine, J. G. Brown Cancer Center, Molecular Targets Program, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Clark
authors.affiliation: Department of Medicine, J. G. Brown Cancer Center, Molecular Targets Program, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rinaldo
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Nelson
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Barnoud
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: M Lee
authors.initials: ML
authors.lastname: Schmidt
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Hobbing
authors.affiliation: National Cancer Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Michele D
authors.initials: MD
authors.lastname: Vos
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Sils
authors.affiliation: Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, USA gjclar01@louisville.edu.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Clark
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D020552:Comet Assay; D004249:DNA Damage; D004260:DNA Repair; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D051716:Replication Protein A / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D051760:Xeroderma Pigmentosum Group A Protein / Q000378:metabolism*
chemical_list: C411762:RASSF1 protein, human; C496882:RASSF1 protein, mouse; D051716:Replication Protein A; D025521:Tumor Suppressor Proteins; C497314:XPA protein, human; D051760:Xeroderma Pigmentosum Group A Protein