Bloom’s Syndrome and Bloom’s Syndrome and Bloom helicaseBloom helicase

Alexandra OttoAlexandra Otto

March 16, 2004March 16, 2004

Bloom SyndromeBloom Syndrome Syndrome was first described by New York dermatologist Syndrome was first described by New York dermatologist

David Bloom in 1954David Bloom in 1954

Extremely rare Extremely rare ~ 220 cases worldwide~ 220 cases worldwide

Death before age 30Death before age 30

Mean age of cancer diagnosis ~ 24Mean age of cancer diagnosis ~ 24

BS is associated with a predisposition to cancers of all typesBS is associated with a predisposition to cancers of all types

Autosomal recessive disorderAutosomal recessive disorder

Arises from a mutation in the gene BLMArises from a mutation in the gene BLM

Clinical Features of BSClinical Features of BS Proportional dwarfismProportional dwarfism Sun-induced erythemaSun-induced erythema

Type-II diabetesType-II diabetes Narrow face and prominent earsNarrow face and prominent ears Male infertility and female sub-fertilityMale infertility and female sub-fertility Frequent infectionsFrequent infections

http://www.skinsite.com/erythema

How was BLM identified?How was BLM identified? Prevalence of BS among the Prevalence of BS among the

Ashkenazi Jewish population (carrier Ashkenazi Jewish population (carrier rate of 1%)rate of 1%)

Used positional cloning (like Rb)Used positional cloning (like Rb)

Maps to chromosome 15q26.1Maps to chromosome 15q26.1

)

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

BLM encodes a helicaseBLM encodes a helicase Helicases are Helicases are

enzymes that enzymes that separate the separate the complementary complementary strands of nucleic-strands of nucleic-acid duplexesacid duplexes

essential for all essential for all aspects of DNA aspects of DNA metabolism metabolism

http://www.blc.arizona.edu/marty/411/Modules/Lectures/Figures/helicase.GIF

The RecQ helicase familyThe RecQ helicase family BLM helicase is a member of the RecQ familyBLM helicase is a member of the RecQ family

RecQ family gets its name from the recQ RecQ family gets its name from the recQ gene in E. coli.gene in E. coli.

Family members share a homologous region Family members share a homologous region with E. coli with E. coli

Conserved region is flanked by stretches of Conserved region is flanked by stretches of amino acids called the N-terminal region and amino acids called the N-terminal region and the C-terminal regionthe C-terminal region

http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg

RecQ helicasesRecQ helicases Unicellular organisms express 1 RecQ Unicellular organisms express 1 RecQ

enzyme whereas humans express 5enzyme whereas humans express 5

Defects in 3 of these human RecQ Defects in 3 of these human RecQ helicases (BLM, WRN, and RECQ4) give helicases (BLM, WRN, and RECQ4) give rise to clinical disorders associated with rise to clinical disorders associated with cancer predispositioncancer predisposition

Bloom’s syndrome, Werner’s syndrome, Bloom’s syndrome, Werner’s syndrome, and Rothmund-Thomson syndromeand Rothmund-Thomson syndrome

Role of Bloom helicaseRole of Bloom helicase Required for the maintenance of Required for the maintenance of

genomic integritygenomic integrity Duplex unwindingDuplex unwinding ‘‘Caretaker’ tumor-suppressorCaretaker’ tumor-suppressor Caretakers influence genomic Caretakers influence genomic

stability without directly regulating stability without directly regulating tumorigenesistumorigenesis

Repair of double-strand breaksRepair of double-strand breaks

http://nar.oupjournals.org/cgi/content/full/31/21/6272

Role of BLM helicaseRole of BLM helicase bloom helicase normally plays a role in the bloom helicase normally plays a role in the

repair of DSB by the homologous repair of DSB by the homologous recombination pathway recombination pathway

In Bloom’s syndrome cells, repair may occur In Bloom’s syndrome cells, repair may occur through the error-prone NHEJ pathway through the error-prone NHEJ pathway

increased genomic instability and increased genomic instability and predisposition to malignancy.predisposition to malignancy.

BLM helicase has not been placed at an BLM helicase has not been placed at an exact step in the HR pathwayexact step in the HR pathway

Possible roles of BLMPossible roles of BLM Ability to process recombination Ability to process recombination

intermediates during DNA replicationintermediates during DNA replication- G-quadruplexes, hairpins- 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 BLM helicase as a roadblock removerroadblock remover

..

http://www.biochemj.org/bj/374/0577/bj3740577.htm

Branch migrationBranch migration

http://www.biochemj.org/bj/374/0577/bj3740577.htm

Interaction with crucial Interaction with crucial proteinsproteins

BLM has not been definitively placed at a certain step in the BLM has not been definitively placed at a certain step in the homologoushomologous recombination pathway, but is known to interact with a recombination pathway, but is known to interact with a number of crucial proteinsnumber of crucial proteins

http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg

Features of BLM helicase Features of BLM helicase mutantsmutants

Abnormal DNA replicationAbnormal DNA replication Elevated level of homologous recombinationElevated level of homologous recombination

In Bloom’s syndrome cellsIn Bloom’s syndrome cells → → accumulation of abnormal replication accumulation of abnormal replication intermediatesintermediates → → increase in the frequency of reciprocal increase in the frequency of reciprocal exchangesexchanges → → ~ 10 fold increase in sister-chromatid ~ 10 fold increase in sister-chromatid exchangesexchanges

Mouse ModelMouse ModelKnockout miceKnockout mice

- death by extreme anemia at 13.5 days - death by extreme anemia at 13.5 days - immortalized cell line showed a high frequency of sister chromatid- immortalized cell line showed a high frequency of sister chromatid exchangeexchange- characteristic short stature is seen in early stages of embryo- characteristic short stature is seen in early stages of embryo developmentdevelopment

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 PredispositionCancer PredispositionWhat features of hyper-recombination What features of hyper-recombination

underlie theunderlie thecancer predisposition?cancer predisposition? Recombination events are not carried out Recombination events are not carried out

with perfect fidelitywith perfect fidelity Events are not carried out to completionEvents are not carried out to completionThis leads to:This leads to: Chromosomal duplication or breakage Chromosomal duplication or breakage Genomic instability and therefore cancerGenomic instability and therefore cancer

BLM helicase and cancerBLM helicase and cancerConcluding pointsConcluding points BLM helicase is a caretaker tumor suppressorBLM helicase is a caretaker tumor suppressor Proposed to act in HR pathwayProposed to act in HR pathway Homologous recombination exists to repair double Homologous recombination exists to repair double

strand breaks and damaged replication forksstrand breaks and damaged replication forks Sister chromatid exchanges arise during HR from the Sister chromatid exchanges arise during HR from the

crossing over of chromatid armscrossing over of chromatid arms BS cells have high frequency of SCEBS cells have high frequency of SCE This hyper-recombination results from defective This hyper-recombination results from defective

replicationreplication Without BLM helicase, replication cannot proceed Without BLM helicase, replication cannot proceed

smoothlysmoothly Genomic instability → CANCER predispositionGenomic instability → CANCER predisposition Cancer of all types because all cells need to repair Cancer of all types because all cells need to repair

damages in replication machinarydamages in replication machinary

Works CitedWorks Citedhttp://www.ncbi.nlm.nih.govhttp://www.ncbi.nlm.nih.govhttp://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpghttp://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpghttp://http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmdwww.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd==Retrieve&dbRetrieve&db==

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n58/full/1205959a.htmhttp://tmm.trends.comhttp://www.biomedcentral.com/1471-2121/4/15