07:27am Saturday 22 February 2020

Human Genes Repaired Using Paired Chromosome as Template, Say University of Pittsburgh Scientists

The broken ends of the DNA strands are not merely stuck back together as had been thought, they said in a report published online this week in Early Edition of the Proceedings of the National Academy of Sciences.

Many studies suggest that when the double-stranded DNA in human cells is broken, it is simply rejoined at the broken ends, which is an efficient but error-prone strategy, said Yuri Nikiforov, M.D., Ph.D., professor and director, Division of Anatomic Pathology, Department of Pathology, Pitt School of Medicine. If that were the case, mistakes such as deletion of some of the building blocks of DNA would be made at the repair site that in turn could lead to production of abnormal proteins and other harmful consequences.

“Our new study dramatically changes our understanding of how these breaks are fixed,” Dr. Nikiforov said. “This kind of damage is actually repaired by using the complementary parental gene as a blueprint for rebuilding.”

Each human cell contains 22 paired chromosomes, plus the sex-specific X chromosomes for females and Y for males. These 46 chromosomes contain tens of thousands of genes, and there may be small variations between the versions inherited from each parent. Breaks continuously occur in DNA strands due to routine metabolic processes and exposures to ionizing radiation and other toxins.

The researchers found that when one of the chromosomes was broken in the area of a gene, the matching version of the chromosome from the other parent will get close to it to make contact at the site of the break. The uninjured chromosome’s genetic code is copied to repair the damaged one with great accuracy.

“It’s expected that malfunctioning of this DNA repair mechanism in human cells would lead to greater accumulation of errors in coding genes,” Dr. Nikiforov noted. “It is likely that this observation will help us better understand normal human cellular processes such as aging, as well as harmful conditions such as cancer and other diseases.”

Previous studies of DNA repair looked at the whole genome, but more than 95 percent of it isn’t used to make protein or regulate growth and cellular processes, he said. When damage occurs in those non-coding areas, the simple repair technique of sticking the ends back together doesn’t do any damage. Previous studies reviewed genome-wide repair and may have overlooked the sophisticated strategy that is used to fix problems in the small fraction of gene-encoding DNA, the researchers said.

Co-authors include Manoj Gandhi, M.D., Ph.D., Viktoria N. Evdokimova, Ph.D., Lindsey Kelly, B.S., Marina N. Nikiforova, M.D., and Christopher J. Bakkenist, Ph.D., all of the University of Pittsburgh School of Medicine; Karen T. Cuenco, Ph.D., of the University of Pittsburgh School of Dental Medicine and the Graduate School of Public Health; and James R. Stringer, Ph.D., of the University of Cincinnati.

The project was funded by National Institutes of Health grants R01 CA88041 and R01 CA148644, and University of Pittsburgh Cancer Institute support grant P30 CA047904.

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