Abstract
Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2170-2184 |
| Number of pages | 15 |
| Journal | Cell reports |
| Volume | 15 |
| Issue number | 10 |
| DOIs | |
| State | Published - Jun 7 2016 |
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Keywords
- ATR
- Cutaneous T cell lymphoma
- POT1
- Replication stress
- Telomere
- Thymic lymphoma
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
}
Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis. / Pinzaru, Alexandra M.; Hom, Robert A.; Beal, Angela; Phillips, Aaron F.; Ni, Eric; Cardozo, Timothy; Nair, Nidhi; Choi, Jaehyuk; Wuttke, Deborah S.; Sfeir, Agnel; Denchi, Eros Lazzerini.
In: Cell reports, Vol. 15, No. 10, 07.06.2016, p. 2170-2184.Research output: Contribution to journal › Article
TY - JOUR
T1 - Telomere Replication Stress Induced by POT1 Inactivation Accelerates Tumorigenesis
AU - Pinzaru, Alexandra M.
AU - Hom, Robert A.
AU - Beal, Angela
AU - Phillips, Aaron F.
AU - Ni, Eric
AU - Cardozo, Timothy
AU - Nair, Nidhi
AU - Choi, Jaehyuk
AU - Wuttke, Deborah S.
AU - Sfeir, Agnel
AU - Denchi, Eros Lazzerini
PY - 2016/6/7
Y1 - 2016/6/7
N2 - Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.
AB - Genome sequencing studies have revealed a number of cancer-associated mutations in the telomere-binding factor POT1. Here, we show that when combined with p53 deficiency, depletion of murine POT1a in common lymphoid progenitor cells fosters genetic instability, accelerates the onset, and increases the severity of T cell lymphomas. In parallel, we examined human and mouse cells carrying POT1 mutations found in cutaneous T cell lymphoma (CTCL) patients. Inhibition of POT1 activates ATR-dependent DNA damage signaling and induces telomere fragility, replication fork stalling, and telomere elongation. Our data suggest that these phenotypes are linked to impaired CST (CTC1-STN1-TEN1) function at telomeres. Lastly, we show that proliferation of cancer cells lacking POT1 is enabled by the attenuation of the ATR kinase pathway. These results uncover a role for defective telomere replication during tumorigenesis.
KW - ATR
KW - Cutaneous T cell lymphoma
KW - POT1
KW - Replication stress
KW - Telomere
KW - Thymic lymphoma
UR - http://www.scopus.com/inward/record.url?scp=84969780102&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84969780102&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.05.008
DO - 10.1016/j.celrep.2016.05.008
M3 - Article
C2 - 27239034
AN - SCOPUS:84969780102
VL - 15
SP - 2170
EP - 2184
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 10
ER -