Study on the functions of BRCA2 in the telomere maintenance : 암 억제인자 BRCA2 에 의한 텔로미어 유지기작 연구

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자연과학대학 생명과학부
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서울대학교 대학원
BRCA2telomeregenetic instabilitytumorigenesisALT
학위논문 (박사)-- 서울대학교 대학원 : 생명과학부, 2013. 2. 이현숙.
Germ-line mutations in BRCA2 predispose humans to cancers in the breast, ovary, and pancreas. Since BRCA2 is a key mediator of homologous recombination (HR) regulating Rad51 recombinase, absence of BRCA2 results in the accumulation of spontaneous gross chromosomal rearrangements (GCR) such as translocations, deletions, inversions and amplifications, which promotes tumorigenesis. It has been thought that such genetic alterations are originated from BRCA2s functional defect in HR or Stalled replication fork protection.

Here, I suggest that BRCA2 is involved in the maintenance of telomere homeostasis. Furthermore, absence of BRCA2 in a telomerase-deficient organism induces Alternative lengthening of telomeres (ALT), which is the alternative mechanism to protect itself from critical telomere shortening independent from telomerase.

Dysfunctional telomeres occurred in BRCA2-deficient cells in the form of end-to-end fusions, signal free ends, and anaphase bridges. I observed telomere length rapid deletion (TRD) in BRCA2-deficient MEFs, which is responsible for end chromosomal fusions. In search for the mechanistic basis of telomere shortening in the absence of BRCA2, I found that the replication fork stalling in telomeres was more profound compared to the non-telomeric region in BRCA2-knockout MEFs. For BRCA2 to function at telomeres, ATR was required. Specifically, BRCA2 has a role in facilitating G-rich lagging strand synthesis at telomeres, by blocking stalled replication fork degradation. Moreover, the fidelity of telomeric DNA replication is impaired in BRCA2-lacking condition. Theses data demonstrate that BRCA2 is required for the prevention of replication fork collapse at the telomeres. Accordingly, I conclude that the tumor suppressive function of BRCA2 involves the role at the telomere replication homeostasis.

If BRCA2 absence results in telomere shortening, how can BRCA2-deficient cells transform? By using the C. elegans model organism, I show that C. elegans brc-2, an orthologue of BRCA2 suppresses the induction of ALT. brc-2 RNAi in trt-1(ok410) overcomes the short life-span in trt-1 mutant worms. trt-1
brc-2 (RNAi) was capable of maintaining telomere length and displayed increased c-circles, indicating that ALT was induced. These results indicate that absence of BRCA2 causes shortening of telomeres. Then at a critical point, absence of BRCA2 induces ALT, strongly suggesting that BRCA2 is the long-sought suppressor of ALT.

My study has shown how telomere shortening can induce genetic instability. Furthermore, these findings that BRCA2 is a suppressor of ALT implies how dysfunctional BRCA2 leads to cancer.
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College of Natural Sciences (자연과학대학)Dept. of Biological Sciences (생명과학부)Theses (Ph.D. / Sc.D._생명과학부)
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