No abstract

DNA charge transport chemistry offers a means of long range, rapid redox signaling. Here we demonstrate that the [4Fe4S] cluster in human DNA primase can utilize this chemistry to coordinate the first steps of replication. Through DNA electrochemistry, we find that a change in oxidation state of the [4Fe4S] cluster acts as a switch for DNA binding. Single-atom mutations that inhibit this charge transfer, moreover, hinder primase initiation without affecting primase structure or polymerization. Generating a single base mismatch in the growing primer duplex, which attenuates DNA charge transport, inhibits primer truncation. Thus redox signaling by [4Fe4S] clusters using DNA charge transport regulates primase binding to DNA and illustrates chemistry that may efficiently drive substrate handoff between polymerases during DNA replication.

We evaluated the influence of family history on longevity by examining longevity in a cohort of 78,994 individuals drawn from the Utah Population Database (UPDB) who were born between 1870 and 1907, and lived to at least age 65. We examined Mendelian genetic and social modes of transmission of excess longevity (the difference between observed and expected longevity) by varying weighted kinship contributions over different classes of relatives. The genetic component of the variation in excess longevity measured as heritability, h2, was approximately 0.15 (95% confidence interval [CI] 0.12-0.18). Among siblings of probands who reached the 97th percentile of excess longevity (+ 14.8 years, currently age 95 for men and 97 for women), the relative risk of recurrence (lambdas) was 2.30 (95% CI 2.08-2.56). In sibships whose relatives were in the top 15% of the distribution for familial excess longevity, the value of lambdas increased substantially, indicating that considering the longevity of distant relatives may be helpful in the selection of families in which to identify genes influencing aging and longevity.

BACKGROUNDIt is well known that genetic variability affects the risk of many cancers, but details of the patterning of inherited cancer risk across different sites and age groups still are not well quantified.METHODSThe authors conducted a nested case–control study of the familial risk of 40 cancers based on a cohort of 662,515 individuals from the Utah Population Database. From 1 to 10 controls selected from the cohort were matched individually on gender, birth year, and birthplace to each cancer case; and familial standardized incidence ratios (FSIR) were calculated for both cases and controls. Conditional logistic regression was used to estimate relative risks and population‐attributable risks (PARs) of cancer in relation to FSIR. Relative risks of cancer in first‐degree through fifth‐degree relatives of cases, compared with controls, were calculated using the proportional hazards methods. All analyses were adjusted for spouse affection status and Latter Day Saints church affiliation.RESULTSThirty‐five of 40 cancers exhibited positive associations between risk and FSIR, and 21 of those associations were statistically significant. PAR estimates were strikingly high for prostate carcinoma (57%), breast carcinoma (39%), colon carcinoma (32%), lip carcinoma (31%), chronic lymphocytic leukemia (35%), and melanoma (32%). Both the proportion and the number of all cancers attributable to family history peaked at 32% in the group ages 65–84 years and remained high in the group age ≥ 85 years.CONCLUSIONSA substantial portion of cancer risk was attributable to familial factors. The patterns of familial cancer recurrence among distant relatives suggested that simple genetic mechanisms may explain much of the familiality of cancer. Cancer 2005. © 2005 American Cancer Society.