title: ATR suppresses endogenous DNA damage and allows completion of homologous recombination repair.
abstract: DNA replication fork stalling or collapse that arises from endogenous damage poses a serious threat to genome stability, but cells invoke an intricate signaling cascade referred to as the DNA damage response (DDR) to prevent such damage. The gene product ataxia telangiectasia and Rad3-related (ATR) responds primarily to replication stress by regulating cell cycle checkpoint control, yet it's role in DNA repair, particularly homologous recombination (HR), remains unclear. This is of particular interest since HR is one way in which replication restart can occur in the presence of a stalled or collapsed fork. Hypomorphic mutations in human ATR cause the rare autosomal-recessive disease Seckel syndrome, and complete loss of Atr in mice leads to embryonic lethality. We recently adapted the in vivo murine pink-eyed unstable (pun) assay for measuring HR frequency to be able to investigate the role of essential genes on HR using a conditional Cre/loxP system. Our system allows for the unique opportunity to test the effect of ATR loss on HR in somatic cells under physiological conditions. Using this system, we provide evidence that retinal pigment epithelium (RPE) cells lacking ATR have decreased density with abnormal morphology, a decreased frequency of HR and an increased level of chromosomal damage.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Brown
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Sager
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Aparna
authors.initials: A
authors.lastname: Gorthi
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Sonal S
authors.initials: SS
authors.lastname: Tonapi
authors.affiliation: Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Brown
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America; Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, Texas, United States of America.
authors.forename: Alexander J R
authors.initials: AJ
authors.lastname: Bishop
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D043171:Chromosomal Instability; D004249:DNA Damage; D005123:Eye / Q000033:anatomy & histology; D017353:Gene Deletion; D059765:Homologous Recombination; D051379:Mice; D018345:Mice, Knockout; D010641:Phenotype; D059767:Recombinational DNA Repair; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000378:metabolism
chemical_list: C576897:Atr protein, mouse; D064007:Ataxia Telangiectasia Mutated Proteins