000131418 001__ 131418
000131418 005__ 20240208155436.0
000131418 0247_ $$2doi$$a10.1182/blood-2017-01-764274
000131418 0248_ $$2sideral$$a136813
000131418 037__ $$aART-2017-136813
000131418 041__ $$aeng
000131418 100__ $$aMartín-Pardillos, Ana
000131418 245__ $$aGenomic and functional integrity of the hematopoietic system requires tolerance of oxidative DNA lesions
000131418 260__ $$c2017
000131418 5060_ $$aAccess copy available to the general public$$fUnrestricted
000131418 5203_ $$aEndogenous DNA damage is causally associated with the functional decline and transformation of stem cells that characterize aging. DNA lesions that have escaped DNA repair can induce replication stress and genomic breaks that induce senescence and apoptosis. It is not clear how stem and proliferating cells cope with accumulating endogenous DNA lesions and how these ultimately affect the physiology of cells and tissues. Here we have addressed these questions by investigating the hematopoietic system of mice deficient for Rev1, a core factor in DNA translesion synthesis (TLS), the postreplicative bypass of damaged nucleotides. Rev1 hematopoietic stem and progenitor cells displayed compromised proliferation, and replication stress that could be rescued with an antioxidant. The additional disruption of Xpc, essential for global-genome nucleotide excision repair (ggNER) of helix-distorting nucleotide lesions, resulted in the perinatal loss of hematopoietic stem cells, progressive loss of bone marrow, and fatal aplastic anemia between 3 and 4 months of age. This was associated with replication stress, genomic breaks, DNA damage signaling, senescence, and apoptosis in bone marrow. Surprisingly, the collapse of the Rev1Xpc bone marrow was associated with progressive mitochondrial dysfunction and consequent exacerbation of oxidative stress. These data reveal that, to protect its genomic and functional integrity, the hematopoietic system critically depends on the combined activities of repair and replication of helix-distorting oxidative nucleotide lesions by ggNER and Rev1-dependent TLS, respectively. The error-prone nature of TLS may provide mechanistic understanding of the accumulation of mutations in the hematopoietic system upon aging.
000131418 540__ $$9info:eu-repo/semantics/openAccess$$aAll rights reserved$$uhttp://www.europeana.eu/rights/rr-f/
000131418 590__ $$a15.132$$b2017
000131418 591__ $$aHEMATOLOGY$$b2 / 71 = 0.028$$c2017$$dQ1$$eT1
000131418 592__ $$a6.434$$b2017
000131418 593__ $$aBiochemistry$$c2017$$dQ1
000131418 593__ $$aImmunology$$c2017$$dQ1
000131418 593__ $$aHematology$$c2017$$dQ1
000131418 593__ $$aCell Biology$$c2017$$dQ1
000131418 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000131418 700__ $$aTsaalbi-Shtylik, Anastasia
000131418 700__ $$aChen, Si
000131418 700__ $$aLazare, Seka
000131418 700__ $$aOs, Ronald P. van
000131418 700__ $$aDethmers-Ausema, Albertina
000131418 700__ $$aFakouri, Nima Borhan
000131418 700__ $$aBosshard, Matthias
000131418 700__ $$aAprigliano, Rossana
000131418 700__ $$aLoon, Barbara van
000131418 700__ $$aSalvatori, Daniela C. F.
000131418 700__ $$aHashimoto, Keiji
000131418 700__ $$aDingemanse-van der Spek, Celia
000131418 700__ $$aMoriya, Masaaki
000131418 700__ $$aRasmussen, Lene Juel
000131418 700__ $$ade Haan, Gerald
000131418 700__ $$aRaaijmakers, Marc H. G. P.
000131418 700__ $$ade Wind, Niels
000131418 773__ $$g130, 13 (2017), 1523-1534$$pBlood$$tBlood$$x0006-4971
000131418 8564_ $$s6647063$$uhttps://zaguan.unizar.es/record/131418/files/texto_completo.pdf$$yVersión publicada
000131418 8564_ $$s3099105$$uhttps://zaguan.unizar.es/record/131418/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000131418 909CO $$ooai:zaguan.unizar.es:131418$$particulos$$pdriver
000131418 951__ $$a2024-02-08-14:39:53
000131418 980__ $$aARTICLE