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DIR Papers of the Month

By Eddy Ball
March 2007

Unique Substrate Specificity of DNA Polymerase Mu

Scientists from the Laboratory of Structural Biology and Laboratory of Molecular Genetics have demonstrated substrate interactions unique to polymerase mu (pol µ), an enzyme involved in a type of DNA repair called nonhomologous DNA end-joining (NHEJ). The NIEHS-funded study appeared in the January 2007 issue of Nature Structural & Molecular Biology.

Pol µ is one of four closely related members of the family X DNA polymerases in mammals. These enzymes participate in the repair of double-strand breaks (DSBs) in DNA in order to maintain stability and replicate large genomes. Anomalies in the repair of DSBs can lead to mutations and threaten the viability of an organism. While studies have demonstrated that pol µ associates with end-joining factors in vitro and is able to repair gapped intermediates in an NHEJ reaction, the specific substrate interactions of pol µ have not been well understood. Investigators had previously explained structures for the remaining family members, polymerase beta (pol ß), polymerase lambda (pol λ) and terminal deoxyribonucleotidyl transferase (TdT).

In this experiment, the research team crystallized the polymerization domain of mouse pol µ and described its structure. The study found substrate interactions and functions that differ from those found in pol ß, pol λ and TdT in several notable ways that may prove biologically relevant.

Citation: Moon AF, Garcia-Diaz M, Bebenek K, Davis BJ, Zhong X, Ramsden DA, Kunkel TA, Pedersen LC. 2007. Structural insight into the substrate specificity of DNA Polymerase µ. Nat Struct Mol Biol 14(1):45-53.

Receptor Regulation in Liver Regeneration

Scientists in the Pharmacogenetics Section of the Laboratory of Reproductive and Developmental Toxicology have demonstrated the therapeutic potential of phenobarbital (PB) treatment in the modulation of liver regeneration. The NIEHS-supported study, published in the January 2007 issue of The Journal of Pharmacology and Experimental Therapeutics, investigated the regulation of the enzyme type 1 diodinase (D1) and thyroid hormone activity in the regenerating mouse liver by constitutive active/androstane receptor (CAR).

Researchers experimented with wild type and CAR-knockout mice following partial hepatectomy (PH) and treatment with PB. Liver injury increased levels of reverse triiodothyronine (rT3), which in turn repressed the expression of key thyroid-regulated genes in the liver. This increase in rT3 may also be involved in a slight decrease in levels of total tetraiodothyronine (T4), the most common thyroid hormone. Treatment with PB normalized rT3 levels and levels of D1 in a CAR-dependent manner, but only in wild type mice.

Thyroid hormone has a well established role in liver regeneration and energy use. These hormones regulate genes involved in the metabolism of sugars and fatty acids. This research demonstrates that PB or other CAR activators may restore normal biosynthesis of thyroid hormones and help the liver regenerate following such events as transplantation, chemical exposure and physical injury or resection.

Citation: Tien ES, Matsui K, Moore R, Negishi M. 2007.The nuclear receptor constitutively active/androstane receptor regulates type 1 deiodinase and thyroid hormone activity in the regenerating mouse liver. J Pharmacol Exp Ther 320(1):307-313.

Cancer and Organochlorine Insecticides

In a study funded by NIEHS and the National Cancer Institute, epidemiologists investigated the relationship between site-specific cancer incidence and organochlorine (OC) insecticide use among private pesticide applicators,primarily farmers, in Iowa and North Carolina enrolled in the Agricultural Health Study (AHS).

The seven OC chemicals included in the study were aldrin, chlordane, DDT, dieldrin, heptachlor, lindane and toxaphene. The chemicals were widely used in agriculture between the 1940s and 1960s. State and federal regulations banned or limited their use in the 1970s and 1980s because of concerns over their environmental persistence and possible health effects.

The scientists examined data from 25,291 participants who had completed a take-home questionnaire eliciting information on comprehensive exposure to 22 pesticides in addition to the detailed information on 22 pesticidesprovided during enrollment. The researchers identified cancers through December 31, 2002, using cancer registries from Iowa and North Carolina.

The study, which appeared in print in the February 2007 issue of the International Journal of Cancer, did not find any clear relationship between cancer risk and the use of this group of insecticides. The researchers did, however, observe associations among specific chemicals, some of which are supported by previous research and warrant further investigation.

Citation: Purdue MP, Hoppin JA, Blair A, Dosemeci M, Alavanja MC. 2007. Occupational exposure to organochlorine insecticides and cancer incidence in the Agricultural Health Study. Int J Cancer 120(3):642-649.

Organochlorines and Breast Cancer among African-American Women

A team of researchers that included NIEHS Senior Investigator Matthew Longnecker, M.D., found no significant association between levels of two organochlorines (OCs) in blood and breast cancer risk in a study of African-American women. Their research, funded partially by NIEHS and published in the February 2007 issue of Cancer Causes and Control, is the largest case-control study of African-American women to date and the first to examine factors related to tumor status.

The team selected 355 cancer patients and 327 controls from the African-American women participating in the Los Angeles component of the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based, case-control study of lifestyle factors and breast cancer risk. Participants provided serum samples, which were analyzed for levels of two common OCs, polychlorinated biphenyls (PCBs) and dichlorodiphenyldichloroethenes (DDE), the metabolite of the pesticide DDT. The researchers also obtained status in regard to estrogen receptor (ER) and progesterone receptor (PR), p53 and HER-2/neu gene over-expression, and chemotherapy.

"This study did not find an increased risk of breast cancer in African-American women from PCBs or DDE at the levels measured in serum, nor was there evidence for effect modification by tumor ER or PR status, or HER-2/neu or p53 expression," the researchers concluded.

Citation: Gatto NM, Longnecker MP, Press MF, Sullivan-Halley J, McKean-Cowdin R, Bernstein L. 2007. Serum organochlorines and breast cancer: a case-control study among African-American women. Cancer Causes Control 18(1):29-39.

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