FANCC suppresses short telomere-initiated telomere sister chromatid exchange.
Telomere shortening has been linked to rare human disorders that present with bone marrow failure including Fanconi anemia (FA). FANCC is one of the most commonly mutated FA genes in FA patients and the FANCC subtype tends to have a relatively early onset of bone marrow failure and hematologic malignancies. Here, we studied the role of Fancc in telomere length regulation in mice. Deletion of Fancc (Fancc(-/-)) did not affect telomerase activity, telomere length or telomeric end-capping in a mouse strain possessing intrinsically long telomeres. However, ablation of Fancc did exacerbate telomere attrition when murine bone marrow cells experienced high cell turnover after serial transplantation. When Fancc(-/-) mice were crossed into a telomerase reverse transcriptase heterozygous or null background (Tert(+/-) or Tert(-/-)) with short telomeres, Fancc deficiency led to an increase in the incidence of telomere sister chromatid exchange. In contrast, these phenotypes were not observed in Tert mutant mice with long telomeres. Our data indicate that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and promotes telomere recombination initiated by short telomeres.
Rhee
David B
DB
Laboratory of Molecular Gerontology, NIH Biomedical Research Center, National Institute on Aging, Baltimore, MD 21224-6825, USA.
Wang
Yisong
Y
Mizesko
Melissa
M
Zhou
Fang
F
Haneline
Laura
L
Liu
Yie
Y
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D005199:Fanconi Anemia / Q000235:genetics; D052218:Fanconi Anemia Complementation Group C Protein / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012854:Sister Chromatid Exchange / Q000235:genetics*; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000235:genetics* / Q000378:metabolism
C497652:Fancc protein, mouse; D052218:Fanconi Anemia Complementation Group C Protein; D019098:Telomerase; C509187:Tert protein, mouse