Cell Survival Depends On Chromosome Integrity

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Cell Survival Depends On Chromosome Integrity

http://www.medicalnewstoday.com/medicalnews.php?newsid=46757

As part of a large National Institutes of Health-funded Technology

Centers for Networks and Pathways project, s Hopkins researchers

have discovered protein machinery important for cells to keep

chromosomes intact. Without such proteins, their experiments show

that yeast cells experience broken chromosomes and DNA damage that in

human cells are well known to lead to cancer.

" Maintaining genome integrity is crucial for cell survival, " says Jef

Boeke, Ph.D., Sc.D., the report's senior author, a professor of

molecular biology and genetics and co-director of the High Throughput

Biology Center of the Institute for Basic Biomedical Sciences at

Hopkins. The report will appear online July 6 in Current Biology.

Boeke and colleagues show that removing from yeast cells two proteins

called sirtuins -- Hst3p and Hst4p -- causes cells to become

hypersensitive to chemical agents and temperature and to

spontaneously break and/or lose chromosomes. In humans, the loss or

breakage of chromosomes can cause cells to lose control of when and

if they are supposed to divide, becoming cancerous.

Nearly every human cell contains about six feet of DNA packaged into

chromosomes. Chromosomes consist of DNA wrapped around a scaffold-

like structure made of proteins called histones. Each time a cell

divides into two, all of this DNA must be copied exactly and

repackaged properly with histones to form chromosomes in the new

cell.

During the copying process, new chromosomes often have breaks in them

that need to be sealed before the chromosome is considered " finished "

and the cell is ready to divide into two. All cells have damage

control mechanisms that can sense nicks and breaks in chromosomes --

DNA damage -- and repair them.

" We think acetylation somehow marks the newly copied DNA so the cell

knows to repair the breaks, " says Boeke. " Once the breaks are

repaired, the acetyl groups no longer are needed and are removed in

normal cells. "

Sirtuins Hst3p and Hst4p are proteins required to remove these

specific chemical " decorations " -- called acetyl groups -- from

specific sites on histones. The acetyl groups are added to lysine-56,

an amino acid in the histone protein chain. Chromosomes in yeast

cells missing Hst3p and Hst4p become hyperacetylated on lysine-56 --

it appears that every lysine-56 in every histone has attached an

acetyl group.

" This is the first time we've ever seen such a huge effect, " says

Boeke. " The chromosomes just light up with acetyl groups -- they're

just saturated " when cells are missing these sirtuins.

Earlier work showed that yeast cells initially need the lysine-56

decorations to repair breaks or other damage to DNA that occur when

the DNA is copied, an essential process that also has the potential

to seriously damage DNA. This new work shows that it is even more

critical for yeast cells to remove these decorations once repair has

been completed. Thus, there is an endless cycle of putting the acetyl

groups on whenever there is damage or the danger thereof and taking

them off again. Failure to take off the " decorations " leads to loss

of entire chromosomes and other problems with the DNA.

Thus, yeast cells need to carefully coordinate acetylation and

deacetylation of lysine-56.

The team concludes that by putting an acetyl group on lysine-56, the

cell is signaling that its DNA is newly made and as a result possibly

contains dangerous breaks. Acetylation on lysine-56 may be a

universal mechanism for cells to mark damaged DNA. DNA damage can be

caused by exposure to chemical mutagens, chemotherapy or even

sunlight.

" There are a million mutagens in our environment, " says Boeke. Once

cells repair the DNA damage, it is important to shut off repair

machinery and return to normal state. The cells require proteins like

the sirtuins Hst3p and Hst4p to act as guideposts to help identify

dangerous DNA lesions. If the DNA repair machinery does not fix these

lesions to maintain chromosome integrity, the cell would lose control

of growth or death.

Moving forward, the team hopes to further understand what controls

these sirtuins to remove acetyl groups and how hyperacetylation can

lead to such dramatic loss of chromosome integrity.

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The High Throughput Biology Center, or HiT Center, of the Institute

for Basic Biomedical Sciences is an interdisciplinary and

interdepartmental effort. The HiT Center combines approaches from a

variety of disciplines including biology, physics, chemistry,

mathematics, computer science and engineering with the goal of

selectively using high-throughput techniques to accelerate hypothesis-

driven research and to speed development of new hypotheses.

The Technology Centers for Networks and Pathways of Lysine

Modification at Hopkins dissects signaling networks and pathways by

developing and applying genetic and computational approaches,

proteomics technologies, mass spectrometry technologies, single-cell

profiling and other novel methods to detect, quantify and monitor

lysine modifications on DNA-coiling histones. Histone modifications

are critical for many biological processes, such as epigenetic

control of gene expression, which itself dictates the expression of

the proteome in all cells. Other lysine modifications include

acetylation, methylation, ubiquitylation and sumoylation.

The researchers were funded by the Ministry of Education, Culture,

Sports, Science and Technology of Japan, Cancer Research UK, the

Association for International Cancer Research, the Canadian

Institutes for Health Research and the National Institutes of Health.

Authors on the paper are: Ivana Celic, Pamela Meluh, Wendell

Griffith, J. Cotter and Boeke of Hopkins; Hiroshi Masumoto of

the Graduate School of Frontier Biosciences at Osaka University,

Japan; and Alain Verreault of the University of Montreal, Canada.

On the

Web:http://www.hopkinsmedicine.org/ibbs/research/HitCenter/index.html