Dr Peter Martin
Cancer and Genome Instability
Biography and research overview
Dr Peter Martin leads a highly collaborative research project, that explores the role of the multi-functional replication checkpoint protein topoisomerase beta binding protein 1 (TOPBP1) in mitosis. He undertook his PhD at the University of Salford after securing the Pathway to Excellence studentship, before joining the Genome Instability and Cancer Group. Dr Martin was awarded the BBSRC Discovery Fellowship to undertake a multidisciplinary research project within the Division of Cancer Biology.
Faithful and accurate division of the genome is vital to prevent damage during every cell cycle. However, cells often acquire DNA entanglements that are observed in mitosis as 'chromatin bridges', linking separating daughter cells, a sub-set of which are termed ultra-fine anaphase bridges (UFBs). If not resolved in a timely manner these bridges are a significant threat to the stability of the genome.
Previously, it was shown that TOPBP1 interacts with topoisomerase 2 alpha (TOP2A), the major human protein associated with the resolution of DNA entanglements in mitosis, and recruits TOP2A to UFBs. Inhibition of TOP2A with doxorubicin or etoposide have become established anti-cancer therapeutic strategies. However, resistance to TOP2A inhibitors as well as bone marrow and cardiac associated toxicity become a therapeutic problem. Dr Martin aims to determine the basis of the TOPBP1 and TOP2A interaction, paving the way towards development of novel anti-cancer therapeutic approaches that directly target mitosis with decreased off target toxicity and increased efficacy.
In collaboration with the Functional Proteomics group, Gene Function group and Division of Structural Biology, Dr Martin is systematically characterising the role of TOPBP1 and its mitotic proteome to provide novel insight into the molecular mechanism of UFB resolution and chromosomal disjunction. The Genome Instability and Cancer Group is the ideal environment for this project, with their extensive expertise in deciphering the molecular processes that underpin genome stability in cells.
Dr Martin aims to establish how healthy and dysfunctional cells facilitate faithful transmission of genetic information to daughter cells, which is necessary for the continuation of all multicellular life.
Related pages
Types of Publications
Journal articles
<jats:p>Endonuclease VIII-like (NEIL) 1 and 3 proteins eliminate oxidative DNA base damage and psoralen DNA interstrand crosslinks through initiation of base excision repair. Current evidence points to a DNA replication associated repair function of NEIL1 and NEIL3, correlating with induced expression of the proteins in S/G2 phases of the cell cycle. However previous attempts to express and purify recombinant human NEIL3 in an active form have been challenging. In this study, both human NEIL1 and NEIL3 have been expressed and purified from E. coli, and the DNA glycosylase activity of these two proteins confirmed using single- and double-stranded DNA oligonucleotide substrates containing the oxidative bases, 5-hydroxyuracil, 8-oxoguanine and thymine glycol. To determine the biochemical role that NEIL1 and NEIL3 play during DNA replication, model replication fork substrates were designed containing the oxidized bases at one of three specific sites relative to the fork. Results indicate that whilst specificity for 5- hydroxyuracil and thymine glycol was observed, NEIL1 acts preferentially on double-stranded DNA, including the damage upstream to the replication fork, whereas NEIL3 preferentially excises oxidized bases from single stranded DNA and within open fork structures. Thus, NEIL1 and NEIL3 act in concert to remove oxidized bases from the replication fork.</jats:p>
<jats:title>Abstract</jats:title><jats:p>Interstrand cross-links (ICLs) are highly cytotoxic DNA lesions that block DNA replication and transcription by preventing strand separation. Previously, we demonstrated that the bacterial and human DNA glycosylases Nei and NEIL1 excise unhooked psoralen-derived ICLs in three-stranded DNA <jats:italic>via</jats:italic> hydrolysis of the glycosidic bond between the crosslinked base and deoxyribose sugar. Furthermore, NEIL3 from <jats:italic>Xenopus laevis</jats:italic> has been shown to cleave psoralen- and abasic site-induced ICLs in <jats:italic>Xenopus</jats:italic> egg extracts. Here we report that human NEIL3 cleaves psoralen-induced DNA-DNA cross-links in three-stranded and four-stranded DNA substrates to generate unhooked DNA fragments containing either an abasic site or a psoralen-thymine monoadduct. Furthermore, while Nei and NEIL1 also cleave a psoralen-induced four-stranded DNA substrate to generate two unhooked DNA duplexes with a nick, NEIL3 targets both DNA strands in the ICL without generating single-strand breaks. The DNA substrate specificities of these Nei-like enzymes imply the occurrence of long uninterrupted three- and four-stranded crosslinked DNA-DNA structures that may originate <jats:italic>in vivo</jats:italic> from DNA replication fork bypass of an ICL. In conclusion, the Nei-like DNA glycosylases unhook psoralen-derived ICLs in various DNA structures <jats:italic>via</jats:italic> a genuine repair mechanism in which complex DNA lesions can be removed without generation of highly toxic double-strand breaks.</jats:p>