Abstract

Familial melanomas comprise 10% of all melanomas. A characteristic feature of melanomas is their strikingly complex genomic profiles, highlighted by genomic rearrangements and chromosome structural aberrations. However, mechanisms responsible for the chromosomal alterations that potentially drive tumorigenesis remain unclear. We postulate that melanomas with mutations disrupting the function of the Protection of Telomere 1 (POT1) protein depend upon the alternative, Lig4-independent NHEJ (A-NHEJ) pathway for DNA repair. We will use mouse models and human tumor samples to understand how progressive telomere dysfunction and activation of the A-NHEJ pathway generate pro-oncogenic chromosomal aberrations and the stepwise accumulation of mutational changes in favor of melanoma initiation and progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA200506-01
Application #
8997583
Study Section
Special Emphasis Panel (ZCA1-SRB-L (O1))
Program Officer
Witkin, Keren L
Project Start
2015-12-16
Project End
2017-11-30
Budget Start
2015-12-16
Budget End
2016-11-30
Support Year
1
Fiscal Year
2016
Total Cost
$181,522
Indirect Cost
$72,772

  Institution

Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Gu, Peili; Jia, Shuting; Takasugi, Taylor et al. (2018) CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length. Aging Cell :e12783
Rai, Rekha; Chang, Sandy (2017) Probing the Telomere Damage Response. Methods Mol Biol 1587:133-138
Gu, P; Wang, Y; Bisht, K K et al. (2017) Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene 36:1939-1951
Hu, Chunyi; Rai, Rekha; Huang, Chenhui et al. (2017) Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Res 27:1485-1502
Chen, Cong; Gu, Peili; Wu, Jian et al. (2017) Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun 8:14929
Rai, Rekha; Chen, Yong; Lei, Ming et al. (2016) TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun 7:10881
Wang, Yang; Wang, Xinwei; Flores, Elsa R et al. (2016) Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 15:646-60