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Intramural Papers of the Month

By Dixie-Ann Sawin and Robin Arnette
November 2009

DNA Scrunching Can Facilitate Repair by Filling the Gaps

Researchers from NIEHS, the University of North Carolina's Lineberger Comprehensive Cancer Center and The Stony Brook University, N.Y., recently provided structural and biochemical evidence that DNA polymerase λ (Pol λ) has been implicated in repair of DNA double-strand breaks by nonhomologous end joining (NHEJ) and base excision repair (BER).

While binding and gap filling by pols β and λ were well characterized for 1-nucleotide gaps, the location of the yet uncopied nucleotides in longer gaps was not known until the recent work by Kunkel and colleagues. In their study, published in the September 2009 issue of Nature Structural and Molecular Biology, they structurally and biochemically elucidated this mechanism, demonstrating that Pol λ fills gaps longer than five or six nucleotides by DNA scrunching.

Like other family X members, pols β, µ, and TdT, it is well suited to fill short gaps in DNA because it can simultaneously bind both ends of the gap: the 3' end by the polymerase domain and the 5' end by the family X polymerase-specific 8 kDa domain. The study demonstrated structurally and biochemically that when filling a 2-nucleotide gap, Pol λ scrunches the template strand and binds the additional uncopied template base in an extrahelical position. This action takes place within a pocket comprising three conserved amino acids. The researchers concluded that, similar to DNA-scrunching by RNA polymerase during transcription initiation, scrunching occurs during DNA repair-associated gap filling synthesis.

Citation: Garcia-Diaz M, Bebenek K, Larrea AA, Havener JM, Perera L, Krahn JM, Pedersen LC, Ramsden DA, Kunkel TA. ( NIEHS 2009. Template strand scrunching during DNA gap repair synthesis by human polymerase lambda. Nat Stuct Mol Biol 16(9):967-972.

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Hippocampal Synaptic Plasticity Can Be Modulated by Differential Calcium Handling

Synaptic plasticity, such as long-term potentiation (LTP), occurs in only some areas of the brain and only during some stages of development. Although the mechanisms involved in the induction of LTP are well known, those involved in its down regulation have not been characterized. Work published in the August 18, 2009 issue of the Proceedings of the National Academy of Sciences, USA (PNAS) by researchers from NIEHS shows that modulation of postsynaptic calcium (Ca2+) concentrations can regulate plasticity in brain regions.

Dudek and colleagues investigated mechanisms that are involved in limiting brain plasticity, using the lack of significant LTP in pyramidal neurons in the CA2 region of the hippocampus as their paradigm. They tested whether Ca2+ handling in these neurons differed significantly from that in CA1 or CA3 pyramidal neurons, which do exhibit robust LTP. Using 2-photon laser scanning microscopy, they demonstrated smaller increases in free intracellular Ca2+ in CA2, compared to CA1 and CA3 neurons. Furthermore, CA2 neurons showed higher Ca2+-buffering capacities and extrusion rates than CA1 or CA3 neurons, resulting in attenuated calcium levels. Blockade of Ca2+ extrusion mechanisms could restore LTP to CA2 neurons.

As further mechanistic characterization, the researchers provide evidence that Pep-19, which is expressed in CA2 neurons, could be involved in regulating Ca2+ extrusion. Additional studies, however, are required to determine the exact role of this protein.

Citation: Simons SB, Escobedo Y, Yasuda R, Dudek SM. ( NIEHS 2009. Regional differences in hippocampal handling provide a cellular mechanism for limiting plasticity. Proc Natl Acad Sci U.S.A. 106(33): 14080-14084.

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UV Radiation Modulates the Expression of Certain Autoimmune Diseases in Women

A recent study concluded that ultraviolet (UV) radiation influenced the relative frequencies of dermatomyositis (DM) and polymyositis (PM), two autoimmune conditions characterized by muscle weakness due to chronic muscle inflammation. Because previous research determined that UV radiation increased expression of the DM-specific Mi-2 autoantigen, the researchers examined whether a relationship existed between UV exposure and the relative frequencies of DM and anti-Mi-2 autoantibodies.

A collaborative team of scientists used information from referral centers that evaluated myositis patients in various regions of the U.S. The data generated from 380 patients suggested that geographic gradients of DM and anti-Mi-2 autoantibodies were related to the intensity of UV radiation at the location of disease onset. These findings were only found in women, suggesting that inherent differences in how men and women respond to UV radiation may play a role in the development of autoimmune disorders.

This work is the first to show that UV radiation may modulate the clinical and immunologic expression of autoimmune disease in women.

Citation: Love LA, Weinberg CR, McConnaughey DR, Oddis CV, Medsger TA, Reveille JD, Arnett FC, Targoff IN, Miller FW. ( NIEHS 2009. Ultraviolet radiation intensity predicts the relative distribution of dermatomyositis and anti-Mi-2 autoantibodies in women. Arthritis Rheum 60(8):2499-2504.

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A Novel Chromosomal Candidate Region for Childhood Asthma

An international team of scientists led by investigators from NIEHS have found evidence that single nucleotide polymorphisms (SNPs) in or near the transducin-like enhancer of split 4 (TLE4) gene on chromosome 9q21.31 are related to prevalence of childhood asthma in the Mexican population. The study represents the first asthma genome-wide association study (GWAS) in Mexicans and the most extensive coverage of genetic variation for an asthma GWAS in any Hispanic population.

The researchers conducted a GWAS in 492 Mexican children with asthma, along with their parents. Eleven of the most associated GWAS SNPs were tested for replication in an independent Mexican case-parent trios study and two SNPs in the 9q21.31 region gave evidence for replication.

Mexicans have a mixture primarily of European and Native American ancestries and ancestry analysis of the 9q chromosomal region suggests that the variants in this region could be related to ethnic differences in asthma risk.

Citation: Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, Li H, del Rio-Navarro BE, Willis-Owens SA, Weiss ST, Raby BA, Gao H, Eng C, Chapela R, Burchard EG, Tang H, Sullivan PF, London SJ. ( NIEHS 2009. Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in Mexican children. PLoS Genet 5(8):e1000623.

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(Dixie-Ann Sawin, Ph.D., is a post-doctoral research fellow in the NIEHS Laboratory of Neurobiology Neurotoxicology Group on detail as a writer for the Environmental Factor.)

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