熊本大学発生医学研究所／ P09-10 【英訳】Division of Developmental Regulation

Cell Maintenance

The Rad18 protein,a built-in survival instinct
Investigating the control panelof this gene to discover the mechanisms
for prevention of carcinogenesis
Our DNA is constantly being damaged.
The reason why we can survive even with such damages in
DNA is that there are mechanisms by which
the replication of damaged DNA is controlled.
Dr. Tateishi aims to elucidate DNA replication mechanisms,
raising expectations for significantly advancing research on
cancer prevention and treatment for accelerated
aging disorders.

Rad18: always working in theinterests of the living system
as a whole
Our DNA is constantly being damaged by UV lightirradiation and other sources. If DNA replication
occurs w it hout t hat damage being repaired,mutagenesis and replication fork collapse may occur
more readily, leading to carcinogenesis and cellulardeat h. For t his reasons, huma ns comepre-programmed with a system to ensure that DNA
is not replicated until the damage has been fully
repaired. There are, however, some cases in which
replication continues without complete repairing ofthe damages. Dr. Tateishi’s research aims to clarify
the complexities of DNA replication mechanisms.
He focuses in particular on a protein called “Rad18.”“We know that, if something should occur to thehuman cells that causes a dangerous situation, one
in which many genes may become damaged, Rad18
works to send signals to replicate DNA nevertheless,even if the DNA is damaged”. In other words, incritical situations in which significant damage has
occurred, Rad18 forces the cells to replicate DNA
despite the damage, and in spite of the inherent riskof the mutations that may occur as a consequence ofsuch replication. It functions to prioritize life,s u r v i v a l , a b ove a l l e l s e , by prot e c t i n g t heall-important cells. “This protein works to protect
the interests, namely the survival, of the living
system as a whole. It’s an intriguing mechanism,”says Dr. Tateishi.

Promoting cellular aging,preventing carcinogenesisthat damage to DNA is not properly repaired. Cellaging, supposed to protect us from cel l
ca rcinogenesis, is consequent ly abnorma l ly
accelerated. They do not start to age upon growing
old; rather, children with these disorders will begin
to show the symptoms of old age before they reachage ten. In recent years, Dr. Tateishi has beenworking on a study focusing on developing atreatment for Cockayne syndrome, one type ofaccelerated aging disease. Working as part of a teamunder the jurisdiction of the Japanese Ministry ofHealth, Labour and Welfare, he is conducting work
designed to translate the findings of research onDNA replication mechanisms into possible clinicaltherapies for this disease.

This research is closely linked to studies into cancer
prevention and treatment.
We are beginning to understand how active aging of
the cells functions to prevent those cells frombecoming cancerous. “Aging has a bad image, but
actually it plays a very important function in theliving body,” explains Dr. Tateishi. The impairmentof DNA replication can be a factor in cell aging. “At
the same time, cell aging may also be provoked if
there is a lack of Rad18 activity. So we need toharness this; cancerous cells aggressively replicate
their DNA, which makes them vulnerable to thestress caused by replication. If we can downregulate
the expression of Rad18, then it may be possible topromote cell aging and thereby halt the progress ofthe cell carcinogenesis.” A Rad18 knockout mouseline showed a decrease in testes (reproductive organ)
weight, suggesting decreased fertility. “What thissuggests is that there is a particular concentration ofcell aging within the germ cells, in which DNA
replication is highly active.” Here, Dr. Tateishi has
found that it is possible, to a certain extent, toprevent carcinogenesis in mouse lines susceptible tocancer by knocking out the Rad18 gene.

“In this research program, we derive fibroblasts frompatients indicating signs of Cockayne syndrome, usethem cells, and try to control aging by adding
inhibitors for it. Then we look to see whether there isany effect.” There are a number of different kinds ofaccelerated aging disorders; research looking at thepotential impact of drugs on such disorders is astep-by-step process. Researchers must first identify
a clear target, then see what happens when we treatt he cel ls w it h a cer tain inhibitor t hat might
downregulate a certain function of a certain gene.
“Developing a new drug that works on an intractabledisease is catering to a very limited market, so it’s
hard for drug companies—private industry, in otherwords—to commit to this kind of research,” notes
Dr. Tateishi. “But that’s exactly why we need to beworking on this. It’s the role of universities to makesteady efforts to find effective one among thecommonly used drugs.

Expectations for discovery
and treatment
for accelerated aging disorders
Accelerated aging disorders occur when DNA repair
mechanism fails to function adequately, meaning

Senior Assistant Professor

Satoshi Tateishi
tate@gpo.kumamoto-u.ac.jp

ProfileObtained Bachelor s degree from Faculty of Science, Shizuoka University.
Received a Ph.D. from Graduate School of Science, Osaka University.
1990 Assistant professor, Institute for Medical Genetics,
Kumamoto University Medical School.
2000 Assistant professor, Division of Organogenesis,
Institute of Molecular Embryology and Genetics.
2003 Senior assistant professor,
Institute of Molecular Embryology and Genetics.

Cells can repair DNA damages

Rad18 regulates DNA polymerase

6UV light
Carcinogenesis

Ionizing radiation
Carcinogens
Oxygen radicals

DNA damages may cause mutation,
alteration of the nucleotide sequence.

18AgingPolη

Apoptosis

Recruited

PCNA

Polδ
DamageReplication
machinery halted

186UPolηPolδReplication resumption
by translesion synthesis

References
Hu, L. et al, Two replication fork maintenance pathways fuseinverted repeats to rearrange chromosomes. Nature 501,569-572 (2013)
Durando, M., Tateishi, S., Vaziri, C. A non-catalytic role of DNApolymerase η in recruiting Rad18 and promoting PCNA
monoubiquitination at stalled replication forks. Nucleic Acids
Res. 41, 3079-3093 (2013)
Nakazawa, Y. et al, Mutations in UVSSA cause UV-sensitive
syndrome and impair RNA polymerase IIo processing intranscription-coupled nucleotide-excision repair. Nat. Genet.
44, 586-592 (2012)
Sun, J. et al, Rad18 is required for long-term maintenance ofspermatogenesis in mouse testes. Mech. Dev. 126, 173-183(2009)

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Cell aging as a strategy to prevent carcinogenesis

Young cells

Maintenance of genomic integrity is necessary for cellular viabilityAged cells

Manipulation of the aging mechanism can lead to cancer therapy.

Normal mouse testis

Rad18-deficient mouse testis

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