Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions
DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1-methylguanine (m1G) and 3-methylcytosine (m3C)...
| Main Authors: | , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Elsevier
2014
|
| Online Access: | http://hdl.handle.net/1721.1/92256 https://orcid.org/0000-0001-6159-0778 https://orcid.org/0000-0002-2196-5691 |
| _version_ | 1811095599937748992 |
|---|---|
| author | Rechkoblit, Olga Delaney, James C. Essigmann, John M. Patel, Dinshaw J. Essigmann, John M. |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Rechkoblit, Olga Delaney, James C. Essigmann, John M. Patel, Dinshaw J. Essigmann, John M. |
| author_sort | Rechkoblit, Olga |
| collection | MIT |
| description | DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1-methylguanine (m1G) and 3-methylcytosine (m3C), with nucleotide incorporation opposite these lesions being predominantly mutagenic. Further, extension after insertion of both correct and incorrect bases, introduces additional base substitution and deletion errors. Crystal structures of the Dpo4 ternary extension complexes with correct and mismatched 3′-terminal primer bases opposite the lesions reveal that both m1G and m3C remain positioned within the DNA template/primer helix. However, both correct and incorrect pairing partners exhibit pronounced primer terminal nucleotide distortion, being primarily evicted from the DNA helix when opposite m1G or misaligned when pairing with m3C. Our studies provide insights into mechanisms related to hindered and mutagenic bypass of methylated lesions and models associated with damage recognition by repair demethylases. |
| first_indexed | 2024-09-23T16:20:32Z |
| format | Article |
| id | mit-1721.1/92256 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:20:32Z |
| publishDate | 2014 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/922562022-09-29T19:36:29Z Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions Rechkoblit, Olga Delaney, James C. Essigmann, John M. Patel, Dinshaw J. Essigmann, John M. Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Chemistry Delaney, James C. Essigmann, John M. DNA is susceptible to alkylation damage by a number of environmental agents that modify the Watson-Crick edge of the bases. Such lesions, if not repaired, may be bypassed by Y-family DNA polymerases. The bypass polymerase Dpo4 is strongly inhibited by 1-methylguanine (m1G) and 3-methylcytosine (m3C), with nucleotide incorporation opposite these lesions being predominantly mutagenic. Further, extension after insertion of both correct and incorrect bases, introduces additional base substitution and deletion errors. Crystal structures of the Dpo4 ternary extension complexes with correct and mismatched 3′-terminal primer bases opposite the lesions reveal that both m1G and m3C remain positioned within the DNA template/primer helix. However, both correct and incorrect pairing partners exhibit pronounced primer terminal nucleotide distortion, being primarily evicted from the DNA helix when opposite m1G or misaligned when pairing with m3C. Our studies provide insights into mechanisms related to hindered and mutagenic bypass of methylated lesions and models associated with damage recognition by repair demethylases. National Institutes of Health (U.S.) (Grant CA80024) United States. Dept. of Energy. Office of Basic Energy Sciences (DE-AC02-06CH11357) National Center for Research Resources (U.S.). Argonne National Laboratory (Award RR-15301) 2014-12-10T17:43:06Z 2014-12-10T17:43:06Z 2011-06 2011-03 Article http://purl.org/eprint/type/JournalArticle 09692126 1848-4186 http://hdl.handle.net/1721.1/92256 Rechkoblit, Olga, James C. Delaney, John M. Essigmann, and Dinshaw J. Patel. “Implications for Damage Recognition During Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions.” Structure 19, no. 6 (June 2011): 821–832. © 2011 Elsevier Ltd. https://orcid.org/0000-0001-6159-0778 https://orcid.org/0000-0002-2196-5691 en_US http://dx.doi.org/10.1016/j.str.2011.03.020 Structure Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Elsevier Elsevier |
| spellingShingle | Rechkoblit, Olga Delaney, James C. Essigmann, John M. Patel, Dinshaw J. Essigmann, John M. Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions |
| title | Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions |
| title_full | Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions |
| title_fullStr | Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions |
| title_full_unstemmed | Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions |
| title_short | Implications for Damage Recognition during Dpo4-Mediated Mutagenic Bypass of m1G and m3C Lesions |
| title_sort | implications for damage recognition during dpo4 mediated mutagenic bypass of m1g and m3c lesions |
| url | http://hdl.handle.net/1721.1/92256 https://orcid.org/0000-0001-6159-0778 https://orcid.org/0000-0002-2196-5691 |
| work_keys_str_mv | AT rechkoblitolga implicationsfordamagerecognitionduringdpo4mediatedmutagenicbypassofm1gandm3clesions AT delaneyjamesc implicationsfordamagerecognitionduringdpo4mediatedmutagenicbypassofm1gandm3clesions AT essigmannjohnm implicationsfordamagerecognitionduringdpo4mediatedmutagenicbypassofm1gandm3clesions AT pateldinshawj implicationsfordamagerecognitionduringdpo4mediatedmutagenicbypassofm1gandm3clesions AT essigmannjohnm implicationsfordamagerecognitionduringdpo4mediatedmutagenicbypassofm1gandm3clesions |