Genome maintenance and transcription integrity in aging and disease

Abstract

DNA damage contributes to cancer development and aging. Congenital syndromes that affect DNA repair processes are characterized by cancer susceptibility, developmental defects, and accelerated aging (Schumacher et al., 2008). DNA damage interferes with DNA metabolism by blocking replication and transcription. DNA polymerase blockage leads to replication arrest and can gives rise to genome instability. Transcription, on the other hand, is an essential process for utilizing the information encoded in the genome. DNA damage that interferes with transcription can lead to apoptosis and cellular senescence. Both processes are powerful tumor suppressors (Bartek and Lukas, 2007). Cellular response mechanisms to stalled RNA polymerase II complexes have only recently started to be uncovered. Transcription-coupled DNA damage responses might thus play important roles for the adjustments to DNA damage accumulation in the aging organism (Garinis et al., 2009). Here we review human disorders that are caused by defects in genome stability to explore the role of DNA damage in aging and disease. We discuss how the nucleotide excision repair system functions at the interface of transcription and repair and conclude with concepts how therapeutic targeting of transcription might be utilized in the treatment of cancer.

Transcriptional Regulation of the Human Genes that Encode DNA Repair- and Mitochondrial Function-Associated Proteins

“…This process begins with unwinding the double stranded DNA by TFIIH, the next step is that the damaged strand is incised apart by XPF, XPG and endonucleases, then gap is filled and finally the nick is ligated [72].…”

Genetics of aging, progeria and lamin disorders

“…Although several cellular pathways have emerged as key players in the process of biological aging, a significant proportion of them eventually converge as the threats being posed on genomic integrity [1,2]. The insults to genomic stability have further evolved as causative factor of several premature aging syndromes like Cockayne syndrome, Werner syndrome, HGPS and many more [3]. Here, we review the genetic alterations leading to progeroid syndromes (especially progeria) and other laminopathies.…”

A C. elegans homolog for the UV-hypersensitivity syndrome disease gene UVSSA

“…TC-NER deficiencies are associated with two photosensitive syndromes: Cockayne syndrome (CS) and UV-hypersensitivity syndrome (UVSS) [9]. CS is characterized by sun sensitivity, developmental delay, short stature, microcephaly, and severe neurological abnormalities.…”