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Ssb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress

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cris.lastimport.scopus2024-02-12T20:09:35Z
dc.abstract.enCombined loss of Ssb1/Ssb2 induces rapid lethality due to replication stress\textendashassociated loss of hematopoietic stem and progenitor cells.Functionally, loss of Ssb1/Ssb2 activates p53 and IFN pathways, causing enforced cell cycling in quiescent HSPCs and apoptotic cell loss.Publisher\textquoterights Note: There is an Inside Blood Commentary on this article in this issue.Hematopoietic stem and progenitor cells (HSPCs) are vulnerable to endogenous damage and defects in DNA repair can limit their function. The 2 single-stranded DNA (ssDNA) binding proteins SSB1 and SSB2 are crucial regulators of the DNA damage response; however, their overlapping roles during normal physiology are incompletely understood. We generated mice in which both Ssb1 and Ssb2 were constitutively or conditionally deleted. Constitutive Ssb1/Ssb2 double knockout (DKO) caused early embryonic lethality, whereas conditional Ssb1/Ssb2 double knockout (cDKO) in adult mice resulted in acute lethality due to bone marrow failure and intestinal atrophy featuring stem and progenitor cell depletion, a phenotype unexpected from the previously reported single knockout models of Ssb1 or Ssb2. Mechanistically, cDKO HSPCs showed altered replication fork dynamics, massive accumulation of DNA damage, genome-wide double-strand breaks enriched at Ssb-binding regions and CpG islands, together with the accumulation of R-loops and cytosolic ssDNA. Transcriptional profiling of cDKO HSPCs revealed the activation of p53 and interferon (IFN) pathways, which enforced cell cycling in quiescent HSPCs, resulting in their apoptotic death. The rapid cell death phenotype was reproducible in in vitro cultured cDKO-hematopoietic stem cells, which were significantly rescued by nucleotide supplementation or after depletion of p53. Collectively, Ssb1 and Ssb2 control crucial aspects of HSPC function, including proliferation and survival in vivo by resolving replicative stress to maintain genomic stability.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorShi, Wei
dc.contributor.authorVu, Therese
dc.contributor.authorBoucher, Didier
dc.contributor.authorNde, Jules
dc.contributor.authorPandita, Raj K.
dc.contributor.authorStraube, Jasmin
dc.contributor.authorBoyle, Glen M.
dc.contributor.authorAl-Ejeh, Fares
dc.contributor.authorNag, Purba
dc.contributor.authorJeffery, Jessie
dc.contributor.authorHarris, Janelle L.
dc.contributor.authorBain, Amanda L.
dc.contributor.authorGrzelak, Marta Monika
dc.contributor.authorMitra, Abhishek
dc.contributor.authorDojer, Norbert
dc.contributor.authorCrosetto, Nicola
dc.contributor.authorCloonan, Nicole
dc.contributor.authorBecherel, Olivier J.
dc.contributor.authorFinnie, John
dc.contributor.authorSkaar, Jeffrey R.
dc.contributor.authorWalkley, Carl R.
dc.contributor.authorPandita, Tej K.
dc.contributor.authorRowicka, Maga
dc.contributor.authorLane, Steven W.
dc.contributor.authorKhanna, Kum Kum
dc.contributor.authorGinalski, Krzysztof
dc.contributor.authorSkrzypczak, Magdalena
dc.contributor.authorBiernacka, Anna
dc.date.accessioned2024-01-26T08:07:28Z
dc.date.available2024-01-26T08:07:28Z
dc.date.issued2017
dc.description.financeNie dotyczy
dc.identifier.doi10.1182/BLOOD-2016-06-725093
dc.identifier.issn0006-4971
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/120539
dc.identifier.weblinkhttp://www.bloodjournal.org/content/129/18/2479
dc.languageeng
dc.pbn.affiliationcomputer and information sciences
dc.relation.ispartofBlood
dc.rightsClosedAccess
dc.sciencecloudnosend
dc.titleSsb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress
dc.typeJournalArticle
dspace.entity.typePublication