DNA damage and repair

2012 senior Scholar Award in aging

The human genome is thought to be a relatively stable entity, although its integrity is under continual threat from transposable elements (TEs). TEs, also known as “parasitic” or “junk” DNA sequences, have about doubled the size of the human genome throughout evolution. The replication of these... >> MORE

2012 senior Scholar Award in aging

Mitochondrial DNA quality control and aging: promoting selective removal of mutant mitochondrial genomes Mitochondria are present in almost all cells, and contain many copies of a small, circular genome (mtDNA). The encoded gene products are all required, directly or indirectly, for oxidative... >> MORE

2012 senior Scholar Award in aging

The literature on aging includes very many papers correlating changes in chromatin structure with aging, including in yeast and mammalian cells. A limitation of these studies is that, until recently, we have had no clear picture of how chromatin architecture is related to gene regulation in... >> MORE

2012 senior Scholar Award in aging

Exposure to chemical and physical agents that damage all of the molecules in our cells and tissues occurs throughout our lifespan, and is inevitable. Such exposure includes agents that inflict damage upon our DNA, in other words our genetic material. These agents come from both natural and... >> MORE

2012 senior Scholar Award in aging

The DNA damage response (DDR) has evolved to monitor the integrity of the genome. Chromosomal rearrangements and mutations are a common characteristic of cancer cells, and components of the DDR machinery are often mutated in cancer. Interestingly, several DDR proteins also target metabolic... >> MORE

2011 senior Scholar Award in aging

A major challenge in basic research on aging is to distinguish among various potential causative influences of age-related diseases. There have been many hypothesis put forward to explain the deterioration of tissue homeostasis and regenerative capacity during aging. Age-induced accumulation of... >> MORE

2010 senior Scholar Award in aging
Genomic instability has been implicated as a major cause of aging. Two of the most dynamic components of the genome are transposon--jumping genes, and telomeres--chromosome ends. Transposon silencing and telomere maintenance therefore represent two fundamental activities that ensure genomic... >> MORE
2009 senior Scholar Award in aging

Genome damage caused by reactive oxygen species has long been though to be associated with aging and neurodegeneration. Because of limitations in available experimental methods, previous work focused on determining the overall levels of various kinds of oxidative damage. It is likely, though,... >> MORE

2008 senior Scholar Award in aging

Identical, also called monozygotic (MZ) twins represent one of natureís extraordinary phenomena. MZ twins are unique with respect to genetic identity: two persons that are derived from a single cell, who can also be treated as a single subject present in two copies. Therefore, they are a... >> MORE

2008 senior Scholar Award in aging
We have studied the role of genomic instability in the determination of lifespan in yeast as a model for replicative senescence in human cells. We recently defined a genetic network of 322 genes and 826 interactions that preserve genome stability during DNA replication. This network suggests that... >> MORE
2008 senior Scholar Award in aging
Several models have been proposed to explain the molecular basis of aging, a prominent one of which involves the damage of nuclear DNA. DNA damage accumulates with age, and genetic defects in DNA repair and DNA damage signaling pathways lead to symptoms of premature aging both in animal models and... >> MORE
2008 senior Scholar Award in aging
DNA damage occurs at thousands of sites in every genome of each human cell every day. Most of this damage arises from oxidative free radicals caused by slight inefficiencies in how our bodies 'burn' food using oxygen. Others sources of DNA damage include ionizing radiation that arises naturally... >> MORE
2008 senior Scholar Award in aging
Many proliferating tissues of long lived animals are organized around a stem cell based strategy. In this strategy, somatic stem cells divide asymmetrically to replenish themselves and to generate proliferative progenitors. Proliferative progenitors are the cells directly responsible for... >> MORE
2006 senior Scholar Award in aging
A major model of aging postulates that DNA mutations accumulate within mitochondria as we age. Mitochondrial DNA (mtDNA) is particularly vulnerable, because mitochondria are a major source of reactive oxygen species, small molecules that can damage DNA. This damage causes mtDNA mutations, whose... >> MORE
2005 senior Scholar Award in aging

It is well established that normal animal cells typically cannot divide in tissue culture indefinitely. Instead, cells that have completed a large number of divisions undergo replicative senescence, a process whereby the duplication of cellular chromosomal DNA comes to an end. The onset of... >> MORE

2005 senior Scholar Award in aging

RNA editing is found in all animals and has a unique role in determining how genes are expressed in the nervous system. Genes, archived in the genomic DNA of every species, express their information by first being made into working copies of messenger RNA (mRNA). mRNAs are expressed, according... >> MORE

2005 senior Scholar Award in aging
Among biological macromolecules the DNA of the genome has a unique position. Unlike other building blocks of macromolecular structures, such as proteins and lipids, DNA molecules cannot be easily replaced by natural turnover. Hence, the need for genomes to rely on advanced maintenance and repair... >> MORE
2000 senior Scholar Award in aging

Recently, the use of a novel approach for specific detection of heteroplasmic mutations in mitochondrial DNA (mtDNA) has surprisingly revealed high copy point mutations (present in up to 50% of mtDNA) at specific positions in the control region of human fibroblast mtDNA from normal old, but not... >> MORE

2000 senior Scholar Award in aging
Accumulation of deleterious alterations in neuronal DNA has been invoked in models for neurological diseases and aging. While there has been a fair amount of speculation, there have been few definitive studies in this important field. We have been studying the excision repair of DNA damage induced... >> MORE
1999 senior Scholar Award in aging
Endogenous DNA damage and spontaneous mutagenesis may be important mechanisms in aging. We are developing mouse strains defective in base excision repair (BER) that cannot repair endogenous DNA damage through knockout of the Xrccl scaffold protein. The Xrccl protein interacts with... >> MORE
2013 new Scholar Award in aging

The accumulation of misfolded proteins contributes to many diseases, ranging from disorders of the eye to neurodegeneration. These protein misfolding and aggregation diseases are strongly associated with aging, suggesting that older cells are unable to effectively clear damaged proteins.... >> MORE

2013 new Scholar Award in aging

Recent advances in technologies for determining DNA sequences have revealed that every human genome contains small deletions, as well as mutations that abolish the function of one of two copies of tens of genes. Such mutations and deletions do not result in complete loss of function, but rather... >> MORE

2013 new Scholar Award in aging

Genome-wide hypomethylation of DNA is a near-universal feature of aging cells and has been proposed to be a major factor contributing to replicative senescence. However, a direct role for the gradual loss of methylation seen during an organism’s lifetime in the aging process has yet to be... >> MORE

2012 new Scholar Award in aging

Although aging is an immensely complicated process, one characteristic of aging is increased susceptibility to cancer, which can result from genetic instability. Our cells are exposed to DNA damaging agents daily, such as UV irradiation, and as we age the ability of our cells to repair these... >> MORE

2012 new Scholar Award in aging

Aging is associated with gradual functional decline of many organs and systems within our bodies. The specific manifestations of aging vary among different tissues, and common biological mechanisms driving natural aging progression have not been established. We aim to examine a key aspect of... >> MORE

2012 new Scholar Award in aging

Aging is a physiological phenomenon associated with significant changes in multiple organs, including hair graying, hearing and memory loss and reduced regeneration ability in the muscle and hematopoietic system. Understanding the molecular mechanisms for aging is imperative for improving the... >> MORE

2011 new Scholar Award in aging

The accumulation of somatic (non-heritable) DNA mutations over time is a hallmark and potential mechanism of aging. Current theory postulates that un-repaired, stochastic DNA damage results in random DNA mutations that accumulate over time within individual cells, and are passed on as these... >> MORE

2011 new Scholar Award in aging

Most of the DNA in our cells exists as a stable double-stranded molecule that is packaged into a compact structure known as chromatin. This compact or 'closed' structure prevents the interaction of the DNA with specific factors. During certain normal cellular activities such as DNA replication,... >> MORE

2010 new Scholar Award in aging

Aging is a complex process, associated with many changes on different levels from single molecules to hormonal regulation of the whole organism. One mechanism believed to be central to the aging of cells and tissues is cumulative damage to cellular macromolecules, such as proteins, lipids and... >> MORE

2010 new Scholar Award in aging
My goal is to identify factors that predispose older individuals to the development of colorectal cancer. The incidence of colorectal cancer increases dramatically after the age of 50. Interestingly, the incidence rates for men and women diverge at this same time point such that relative risk for... >> MORE
2009 new Scholar Award in aging
Loss of reproductive fitness is a hallmark of aging, conserved from yeast to humans. Not only does aging result in fewer progeny, it can also affect ìquality,î as progeny produced late in life may be inviable or otherwise less fit. Women over a certain age are at a higher risk for miscarriages or... >> MORE
2009 new Scholar Award in aging
Accumulation of somatic mutations during our life history contributes to the stochastic nature of aging. Mutations in protein coding genes are widely assumed to alter the genetic code and therefore the structure, regulation or function of proteins within the cell. Surprisingly, many disease-causing... >> MORE
2009 new Scholar Award in aging
Genomic stability is a major factor that influences aging and aging-related diseases. The integrity of the genome is influenced by histones and other chromosomal proteins that package and stabilize the genome as well as regulate gene expression. The posttranslational modifications of histones,... >> MORE
2008 new Scholar Award in aging
While almost half of the human genome is occupied by mobile element-related sequences, LINEs (Long INterspersed Elements, L1s) and their parasites are the only active mobile elements still altering DNA composition and perturbing the stability of the host genome. The best characterized and most well... >> MORE
2007 new Scholar Award in aging
Aging is a complex process that occurs at both organismal and cellular levels. As cells age, DNA damage and mutations accumulate in the genome. Certain defects in DNA repair and telomere maintenance, such as those associated with Werner syndrome and ataxia telangiectasia, lead to premature aging... >> MORE
2006 new Scholar Award in aging
One hallmark of aging cells is a gradual decline in their ability to repair DNA damage, resulting in the accumulation of mutations and genomic rearrangements. Recent data indicate that the fidelity of DNA double-strand break repair may be particularly relevant to the aging process. In general,... >> MORE
2006 new Scholar Award in aging
The DNA damage theory of aging states that accumulation of DNA damage or chromosomal abnormalities over time can lead to decreasing cell function, and that the additive effects of such damage result in aging. This theory has been partially tested using mouse as an experimental system, where mouse... >> MORE
2005 new Scholar Award in aging

Adult somatic stem cells are unspecialized cells that renew themselves for a long period of time, but under certain physiological or experimental conditions, they differentiate through progenitor cells into cells with tissue specific function. Hematopoietic stem cells, which reside in the bone... >> MORE

2005 new Scholar Award in aging
The DNA making up the genetic code in our cells is continuously damaged and repaired. The consequences of not repairing DNA damage are revealed by inherited genetic disorders in which DNA repair pathways are disrupted. In these disorders, there can be either a profound increase in cancer risk or... >> MORE
2004 new Scholar Award in aging

Accumulation of DNA damage and loss of telomere protection contribute significantly to the aging process. The Nbs1, Mre11 and Rad50 complex (NMR) plays an important role in DNA double strand break (DSB) repair and telomere maintenance. Two components of this complex, Nbs1 and Mre11, are mutated... >> MORE

2003 new Scholar Award in aging

Aging cells and tissues accumulate point mutations and genomic rearrangements, consistent with a failing ability to defend their genomes against DNA damage. Rearrangements result primarily from errors in repair of double-strand breaks (DSBs), which arise commonly by breakage of replication forks... >> MORE

2001 new Scholar Award in aging

Genetic studies of human progeric syndromes have enhanced our understanding the molecular mechanisms of the aging process. Werner Syndrome (WS) is the segmental progeria considered to be most similar to natural senescence. WS fibroblasts display premature replicative senescence in culture and... >> MORE

2000 new Scholar Award in aging

Throughout life, our DNA is constantly subject to damage from both environmental agents and endogenous reactive oxygen species. Due to incomplete repair of this damage, changes in DNA accumulate in each cell as time passes. Such changes (mutations) are known to have a role in the etiology of... >> MORE

2000 new Scholar Award in aging

Genome instability has long been proposed to be a major factor in the aging process. The contribution of genome instability to aging is underscored by the finding that several of the segmental progeroid syndromes, which are characterized by early onset of conditions normally associated with... >> MORE

1999 new Scholar Award in aging
During the eukaryotic cell cycle, the genome is duplicated through the process of DNA replication and segregated to daughter cells during the process of mitosis. When the events that coordinate the cell cycle fail to properly operate, abnormal cellular conditions arise. Some of these conditions... >> MORE