Transcript Bloom Helicase

Bloom’s Syndrome and Bloom
helicase
Alexandra Otto
March 16, 2004
Bloom Syndrome

Syndrome was first described by New York dermatologist David Bloom in
1954

Extremely rare
~ 220 cases worldwide

Death before age 30

Mean age of cancer diagnosis ~ 24

BS is associated with a predisposition to cancers of all types

Autosomal recessive disorder

Arises from a mutation in the gene BLM
Clinical Features of BS






Proportional dwarfism
Sun-induced erythema
Type-II diabetes
Narrow face and prominent ears
Male infertility and female sub-fertility
Frequent infections
http://www.skinsite.com/erythema
How was BLM identified?

Prevalence of BS among the Ashkenazi Jewish
population (carrier rate of 1%)

Used positional cloning (like Rb)

Maps to chromosome 15q26.1
)
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM
BLM encodes a helicase

Helicases are enzymes
that separate the
complementary strands of
nucleic-acid duplexes

essential for all aspects of
DNA metabolism
http://www.blc.arizona.edu/marty/411/Modules/Lectures/Figures/helicase.GIF
The RecQ helicase family

BLM helicase is a member of the RecQ family

RecQ family gets its name from the recQ gene in E.
coli.

Family members share a homologous region with E.
coli

Conserved region is flanked by stretches of amino
acids called the N-terminal region and the C-terminal
region
http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg
RecQ helicases

Unicellular organisms express 1 RecQ enzyme
whereas humans express 5

Defects in 3 of these human RecQ helicases
(BLM, WRN, and RECQ4) give rise to clinical
disorders associated with cancer predisposition

Bloom’s syndrome, Werner’s syndrome, and
Rothmund-Thomson syndrome
Role of Bloom helicase





Required for the maintenance of genomic
integrity
Duplex unwinding
‘Caretaker’ tumor-suppressor
Caretakers influence genomic stability without
directly regulating tumorigenesis
Repair of double-strand breaks
http://nar.oupjournals.org/cgi/content/full/31/21/6272
Role of BLM helicase

bloom helicase normally plays a role in the repair of
DSB by the homologous recombination pathway

In Bloom’s syndrome cells, repair may occur through
the error-prone NHEJ pathway

increased genomic instability and predisposition to
malignancy.

BLM helicase has not been placed at an exact step in
the HR pathway
Possible roles of BLM

Ability to process recombination intermediates during
DNA replication
- G-quadruplexes, hairpins
 Bloom helicase could reset
the replication fork by branch
migration
http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg
BLM helicase as a roadblock
remover
.
http://www.biochemj.org/bj/374/0577/bj3740577.htm
Branch migration
http://www.biochemj.org/bj/374/0577/bj3740577.htm
Interaction with crucial proteins
 BLM has not been definitively placed at a certain step in the homologous
recombination pathway, but is known to interact with a number of crucial proteins
http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg
Features of BLM helicase mutants


Abnormal DNA replication
Elevated level of homologous recombination
In Bloom’s syndrome cells
→ accumulation of abnormal replication intermediates
→ increase in the frequency of reciprocal exchanges
→ ~ 10 fold increase in sister-chromatid exchanges
Mouse Model
Knockout mice
- death by extreme anemia at 13.5 days
- immortalized cell line showed a high frequency of sister chromatid
exchange
- characteristic short stature is seen in early stages of embryo
development
Viable BLM-/- Mouse
- elevated rate of mitotic recombination
- high frequency of sister-chromatid exchanges and somatic loss of
heterozygosity
- high cancer incidence (lymphomas, carcinomas, sarcomas)
http://www.weizmann.ac.il/home/ligivol/publications/PNAS%201999.pdf
Cancer Predisposition
What features of hyper-recombination underlie
the
cancer predisposition?


Recombination events are not carried out with perfect
fidelity
Events are not carried out to completion
This leads to:


Chromosomal duplication or breakage
Genomic instability and therefore cancer
BLM helicase and cancer
Concluding points
 BLM helicase is a caretaker tumor suppressor
 Proposed to act in HR pathway
 Homologous recombination exists to repair double strand breaks
and damaged replication forks
 Sister chromatid exchanges arise during HR from the crossing
over of chromatid arms
 BS cells have high frequency of SCE
 This hyper-recombination results from defective replication
 Without BLM helicase, replication cannot proceed smoothly
 Genomic instability → CANCER predisposition
 Cancer of all types because all cells need to repair damages in
replication machinary
Works Cited
http://www.ncbi.nlm.nih.gov
http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abst
ract&list_uids=12691817
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abst
ract&list_uids=12427531
http://www.biochemj.org/bj/374/0577/bj3740577.htm
http://www.mssm.edu/jewish_genetics/genetic_diseases.shtml
http://www.nature.com/cgitaf/DynaPage.taf ?file=/onc/journal/v21/n58/full/1205959a.htm
http://tmm.trends.com
http://www.biomedcentral.com/1471-2121/4/15