Is There a Link Between DNA Polymerase Beta and Cancer?

Starcevic, Daniela; Dalal, Shibani; Sweasy, Joann B.

doi:10.4161/cc.3.8.1062

Cited by 236 publications

(222 citation statements)

References 25 publications

Supporting

Mentioning

218

Contrasting

Unclassified

Order By: Relevance

“…Given the role of pol in maintaining genome integrity and the relation between pol 's malfunction and various diseases (e.g., cancer, premature aging), [50][51][52] pol has attracted many experimental (see ref 53 and references therein) and theoretical investigations. 8,54,[55][56][57] Our prior modeling work of the pol dynamics before and after the chemical step of nucleotidyl transfer reaction using MD 48,[58][59][60][61] and transition path sampling (TPS) 22 employed the CHARMM force field.…”

Section: Introductionmentioning

confidence: 99%

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Arora

Schlick

2005

J. Phys. Chem. B

View full text Add to dashboard Cite

The closing conformational transition of wild-type polymerase bound to DNA template/primer before the chemical step (nucleotidyl transfer reaction) is simulated using the stochastic difference equation (in length version, "SDEL") algorithm that approximates long-time dynamics. The order of the events and the intermediate states during pol 's closing pathway are identified and compared to a separate study of pol using transition path sampling (TPS) (Radhakrishnan, R.; Schlick, T. Proc. Natl. Acad. Sci. USA 2004, 101, 5970-5975). Results highlight the cooperative and subtle conformational changes in the pol active site upon binding the correct substrate that may help explain DNA replication and repair fidelity. These changes involve key residues that differentiate the open from the closed conformation (Asp192, Arg258, Phe272), as well as residues contacting the DNA template/primer strand near the active site (Tyr271, Arg283, Thr292, Tyr296) and residues contacting the and γ phosphates of the incoming nucleotide (Ser180, Arg183, Gly189). This study compliments experimental observations by providing detailed atomistic views of the intermediates along the polymerase closing pathway and by suggesting additional key residues that regulate events prior to or during the chemical reaction. We also show general agreement between two sampling methods (the stochastic difference equation and transition path sampling) and identify methodological challenges involved in the former method relevant to large-scale biomolecular applications. Specifically, SDEL is very quick relative to TPS for obtaining an approximate path of medium resolution and providing qualitative information on the sequence of events; however, associated free energies are likely very costly to obtain because this will require both successful further refinement of the path segments close to the bottlenecks and large computational time.

show abstract

Section: Introductionmentioning

confidence: 99%

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Arora

Schlick

2005

J. Phys. Chem. B

View full text Add to dashboard Cite

show abstract

“…A recent review of the literature 10 indicated that Pol β variants are present in 30% of tumors analyzed to date, but these variants are not present in normal tissue from the same patients. Each of the tumors studied also express the wild type Pol β protein.…”

Section: Pol β β Tumor-associated Variants Are Linked To Cancer Etiologymentioning

confidence: 99%

“…The MBD4 gene maps to chromosome 3q21-22, 35 and the MBD4 protein interacts with MLH1, alteration of which is known to result in HNPCC. 36 Importantly, the MBD4 gene contains one polyA (10) and three polyA (6) repeat tracts in exon 3 within the coding region of the gene. 37,38 Tumors resulting from alteration of mismatch repair genes and with high levels of microsatellite instability (MSI-H) synthesize a truncated MBD4 protein due to mutation of these repeats, as shown in Table 1.…”

mentioning

confidence: 99%

Is Base Excision Repair a Tumor Suppressor Mechanism?

Sweasy¹,

Lang²,

DiMaio³

2006

Cell Cycle

Self Cite

View full text Add to dashboard Cite

The base excision repair pathway is critical for the removal of oxidized and methylated bases from the DNA. Much of this DNA damage arises endogenously, as a result of oxygen metabolism. Several proteins including DNA glycosylases, the APE1 endonuclease, DNA polymerase β and DNA ligase, act in a highly regulated and coordinated manner during base excision repair to excise the base adducts from the DNA and restore the normal DNA sequence. Both germline and tumor-associated variants of genes encoding these proteins have been identified in humans. In many cases, the protein variant has been shown to have properties that could contribute to the development of cancer, suggesting that base excision repair acts as a tumor suppressor mechanism in humans. Limited epidemiological studies are consistent with this view. Our review of the literature indicates that additional laboratory and epidemiological studies of the role of base excision repair in cancer etiology is warranted.

show abstract

“…In 30% cases of cancer, pol beta has mutation (Chen et al 2002;Starcevic et al 2004). Leu22Pro tumor-associated variant of polβ is dRP lyase deficient (Dalal et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…If the polβ protein is being mutated then the function will be altered. It has been noted that more than 30% of the tumor samples studied so far have polβ mutation (Starcevic et al, 2004;Trivedi et al, 2008). Pol β variants, K289M and I260M have functional phenotypes that could be related to the etiology of human cancer (Lang et al, 2003;Dalal et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Khanra

Bhattacharya²,

Bhattacharyya³

2012

Asian Pacific Journal of Cancer Prevention

View full text Add to dashboard Cite

Is There a Link Between DNA Polymerase Beta and Cancer?

Cited by 236 publications

References 25 publications

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Is Base Excision Repair a Tumor Suppressor Mechanism?

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India

Contact Info

Product

Resources

About

Is There a Link Between DNA Polymerase Beta and Cancer?

Cited by 236 publications

References 25 publications

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Conformational Transition Pathway of Polymerase β/DNA upon Binding Correct Incoming Substrate

Is Base Excision Repair a Tumor Suppressor Mechanism?

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ63-123, 208-304) with the Risk Factor of Ovarian Carcinoma in India

Contact Info

Product

Resources

About

Association of a Newly Identified Variant of DNA Polymerase Beta (polβΔ_{63-123, 208-304}) with the Risk Factor of Ovarian Carcinoma in India