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PMID:29522130
| Citation |
'Limpose, KL, Trego, KS, Li, Z, Leung, SW, Sarker, AH, Shah, JA, Ramalingam, SS, Werner, EM, Dynan, WS, Cooper, PK, Corbett, AH and Doetsch, PW (2018) Overexpression of the base excision repair NTHL1 glycosylase causes genomic instability and early cellular hallmarks of cancer. Nucleic Acids Res. ' |
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| Abstract |
Base excision repair (BER), which is initiated by DNA N-glycosylase proteins, is the frontline for repairing potentially mutagenic DNA base damage. The NTHL1 glycosylase, which excises DNA base damage caused by reactive oxygen species, is thought to be a tumor suppressor. However, in addition to NTHL1 loss-of-function mutations, our analysis of cancer genomic datasets reveals that NTHL1 frequently undergoes amplification or upregulation in some cancers. Whether NTHL1 overexpression could contribute to cancer phenotypes has not yet been explored. To address the functional consequences of NTHL1 overexpression, we employed transient overexpression. Both NTHL1 and a catalytically-dead NTHL1 (CATmut) induce DNA damage and genomic instability in non-transformed human bronchial epithelial cells (HBEC) when overexpressed. Strikingly, overexpression of either NTHL1 or CATmut causes replication stress signaling and a decrease in homologous recombination (HR). HBEC cells that overexpress NTHL1 or CATmut acquire the ability to grow in soft agar and exhibit loss of contact inhibition, suggesting that a mechanism independent of NTHL1 catalytic activity contributes to acquisition of cancer-related cellular phenotypes. We provide evidence that NTHL1 interacts with the multifunctional DNA repair protein XPG suggesting that interference with HR is a possible mechanism that contributes to acquisition of early cellular hallmarks of cancer. |
| Links |
PubMed Online version:10.1093/nar/gky162 |
| Keywords |
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Significance
Annotations
| Gene product | Qualifier | GO Term | Evidence Code | with/from | Aspect | Extension | Notes | Status |
|---|---|---|---|---|---|---|---|---|
| GO:0000790: nuclear chromatin |
ECO:0000314: |
C |
Figure 2B explains that NTHL1 is primarily localized in the nucleus. To prove this, they treated cells that over expressed NTHL1-GFP and then treated it with cytoskeletal (CSK) buffer for extraction. NTHL1-GFP ended up surviving the extraction while just GFP alone did not, proving that NTHL1-GFP is localized in the nucleus. |
complete | ||||
Notes
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