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

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dc.contributor.authorShi, W.
dc.contributor.authorVu, T.
dc.contributor.authorBoucher, D.
dc.contributor.authorBiernacka, A.
dc.contributor.authorNde, J.
dc.contributor.authorPandita, R.K.
dc.contributor.authorStraube, J.
dc.contributor.authorBoyle, G.M.
dc.contributor.authorAl-Ejeh, F.
dc.contributor.authorNag, P.
dc.contributor.authorJeffery, J.
dc.contributor.authorHarris, J.L.
dc.contributor.authorBain, A.L.
dc.contributor.authorGrzelak, M.
dc.contributor.authorSkrzypczak, M.
dc.contributor.authorMitra, A.
dc.contributor.authorDojer, N.
dc.contributor.authorCrosetto, N.
dc.contributor.authorCloonan, N.
dc.contributor.authorBecherel, O.J.
dc.contributor.authoret al.
dc.date.issued2017
dc.description.abstractHematopoietic 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.description.statementofresponsibilityWei Shi, Therese Vu, Didier Boucher, Anna Biernacka, Jules Nde, Raj K. Pandita, Jasmin Straube, Glen M. Boyle, Fares Al-Ejeh, Purba Nag, Jessie Jeffery, Janelle L. Harris, Amanda L. Bain, Marta Grzelak, Magdalena Skrzypczak, Abhishek Mitra, Norbert Dojer, Nicola Crosetto, Nicole Cloonan, Olivier J. Becherel, John Finnie, Jeffrey R. Skaar, Carl R. Walkley, Tej K. Pandita, Maga Rowicka, Krzysztof Ginalski, Steven W. Lane, and Kum Kum Khanna
dc.identifier.citationBlood, 2017; 129(18):2471-2478
dc.identifier.doi10.1182/blood-2016-06-725093
dc.identifier.issn0006-4971
dc.identifier.issn1528-0020
dc.identifier.orcidFinnie, J. [0000-0003-2277-1693]
dc.identifier.urihttp://hdl.handle.net/2440/123267
dc.language.isoen
dc.publisherAmerican Society of Hematology
dc.relation.granthttp://purl.org/au-research/grants/nhmrc/1085367
dc.relation.grantNHMRC
dc.rights© 2017 by The American Society of Hematology
dc.source.urihttps://doi.org/10.1182/blood-2016-06-725093
dc.subjectHematopoietic Stem Cells
dc.titleSsb1 and Ssb2 cooperate to regulate mouse hematopoietic stem and progenitor cells by resolving replicative stress
dc.typeJournal article
pubs.publication-statusPublished

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