Abstract:
: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.
journal_name
Bloodjournal_title
Bloodauthors
Shi W,Vu T,Boucher D,Biernacka A,Nde J,Pandita RK,Straube J,Boyle GM,Al-Ejeh F,Nag P,Jeffery J,Harris JL,Bain AL,Grzelak M,Skrzypczak M,Mitra A,Dojer N,Crosetto N,Cloonan N,Becherel OJ,Finnie J,Skaar JR,Walkledoi
10.1182/blood-2016-06-725093subject
Has Abstractpub_date
2017-05-04 00:00:00pages
2479-2492issue
18eissn
0006-4971issn
1528-0020pii
blood-2016-06-725093journal_volume
129pub_type
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