title: Paradoxical delay of senescence upon depletion of BRCA2 in telomerase-deficient worms.
abstract: BRCA2 is a multifunctional tumor suppressor involved in homologous recombination (HR), mitotic checkpoint regulation, and telomere homeostasis. Absence of Brca2 in mice results in progressive shortening of telomeres and senescence, yet cells are prone to neoplastic transformation with elongated telomeres, suggesting that BRCA2 has positive and negative effects on telomere length regulation along the path to tumorigenesis. UsingCaenorhabditis elegansas a model, we show here that depletion of BRC-2, an ortholog of BRCA2, paradoxically delays senescence in telomerase-deficient mutant worms. Telomerase-deficient worms (trt-1) exhibit early replication senescence due to short telomeres. It should be noted that worms mutated inbrc-2are not viable as well due to massive genotoxic insults. However, when BRC-2 is depleted by RNA interference intrt-1mutant worms, the number of generations is unexpectedly increased with telomere length maintained, compared to telomerase mutants. Interestingly, depletion of other HR genes such asrad-51andrad-54exhibited similar effects. In worms doubly deficient of telomerase andbrc-2,rad-51, orrad-54, extra telomeric C-circles were generated, suggesting that abrogation of HR induces an alteration in telomere environment favorable to illegitimate telomere maintenance when telomerase is absent. Collectively, absence of BRC-2 in telomerase-deficient background first leads to telomere shortening, followed by an induction of an as-yet-unknown telomere maintenance pathway, resulting in delay of senescence. The results have implications in the understanding of dysfunctional BRCA2-associated tumorigenesis.
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Kwon
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Jaewon
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Hee-Yeon
authors.initials: HY
authors.lastname: Jeon
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Kwangwoo
authors.initials: K
authors.lastname: Hwang
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Chuna
authors.initials: C
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Junho
authors.initials: J
authors.lastname: Lee
authors.affiliation: Samsung Genome Institute Samsung Medical Center Seoul Korea.
authors.forename: Je-Gun
authors.initials: JG
authors.lastname: Joung
authors.affiliation: Samsung Genome Institute Samsung Medical Center Seoul Korea.
authors.forename: Woong-Yang
authors.initials: WY
authors.lastname: Park
authors.affiliation: Department of Biological Sciences & Institute of Molecular Biology and Genetics (IMBG) Seoul National University Gwanak-Gu Seoul Korea.
authors.forename: Hyunsook
authors.initials: H
authors.lastname: Lee
keywords: C. elegans; breast cancer susceptibility gene 2; homologous recombination; senescence; telomere length; trt‐1