POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells
<p>POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and is overexpressed in many cancers. POLQ inhibitors confer synthetic lethality in HR and Shieldin-deficient cancer cells, which has been proposed to reflect a critical dependence on the DSB repair pathway by...
| Main Authors: | , , , |
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| Format: | Journal article |
| Language: | English |
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Cell Press
2022
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| _version_ | 1797109173244133376 |
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| author | Belan, O Sebald, M Adamowicz, M Higgins, G |
| author_facet | Belan, O Sebald, M Adamowicz, M Higgins, G |
| author_sort | Belan, O |
| collection | OXFORD |
| description | <p>POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and is overexpressed in many cancers. POLQ inhibitors confer synthetic lethality in HR and Shieldin-deficient cancer cells, which has been proposed to reflect a critical dependence on the DSB repair pathway by MMEJ. Whether POLQ also operates independent of MMEJ remains unexplored. Here, we show that POLQ-deficient cells accumulate post-replicative ssDNA gaps upon BRCA1/2 loss or PARP inhibitor treatment. Biochemically, cooperation between POLQ helicase and polymerase activities promotes RPA displacement and ssDNA-gap fill-in, respectively. POLQ is also capable of microhomology-mediated gap skipping (MMGS), which generates deletions during gap repair that resemble the genomic scars prevalent in POLQ overexpressing cancers. Our findings implicate POLQ in mutagenic post-replicative gap sealing, which could drive genome evolution in cancer and whose loss places a critical dependency on HR for gap protection and repair and cellular viability.</p> |
| first_indexed | 2024-03-07T07:36:38Z |
| format | Journal article |
| id | oxford-uuid:8f27582d-393b-4d69-ac82-3d3d9ff60255 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:36:38Z |
| publishDate | 2022 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:8f27582d-393b-4d69-ac82-3d3d9ff602552023-03-17T12:08:54ZPOLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cellsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8f27582d-393b-4d69-ac82-3d3d9ff60255EnglishSymplectic ElementsCell Press2022Belan, OSebald, MAdamowicz, MHiggins, G<p>POLQ is a key effector of DSB repair by microhomology-mediated end-joining (MMEJ) and is overexpressed in many cancers. POLQ inhibitors confer synthetic lethality in HR and Shieldin-deficient cancer cells, which has been proposed to reflect a critical dependence on the DSB repair pathway by MMEJ. Whether POLQ also operates independent of MMEJ remains unexplored. Here, we show that POLQ-deficient cells accumulate post-replicative ssDNA gaps upon BRCA1/2 loss or PARP inhibitor treatment. Biochemically, cooperation between POLQ helicase and polymerase activities promotes RPA displacement and ssDNA-gap fill-in, respectively. POLQ is also capable of microhomology-mediated gap skipping (MMGS), which generates deletions during gap repair that resemble the genomic scars prevalent in POLQ overexpressing cancers. Our findings implicate POLQ in mutagenic post-replicative gap sealing, which could drive genome evolution in cancer and whose loss places a critical dependency on HR for gap protection and repair and cellular viability.</p> |
| spellingShingle | Belan, O Sebald, M Adamowicz, M Higgins, G POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells |
| title | POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells |
| title_full | POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells |
| title_fullStr | POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells |
| title_full_unstemmed | POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells |
| title_short | POLQ seals post-replicative ssDNA gaps to maintain genome stability in BRCA-deficient cancer cells |
| title_sort | polq seals post replicative ssdna gaps to maintain genome stability in brca deficient cancer cells |
| work_keys_str_mv | AT belano polqsealspostreplicativessdnagapstomaintaingenomestabilityinbrcadeficientcancercells AT sebaldm polqsealspostreplicativessdnagapstomaintaingenomestabilityinbrcadeficientcancercells AT adamowiczm polqsealspostreplicativessdnagapstomaintaingenomestabilityinbrcadeficientcancercells AT higginsg polqsealspostreplicativessdnagapstomaintaingenomestabilityinbrcadeficientcancercells |