Bloom’s Syndrome and Bloom helicase Alexandra Otto March 16, 2004.
Transcript of Bloom’s Syndrome and Bloom helicase Alexandra Otto March 16, 2004.
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 gene RecQ family gets its name from the recQ gene in E. coli.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 Predisposition
What features of hyper-recombination What features of hyper-recombination underlie theunderlie the
cancer 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 completion
This 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 cancer
Concluding 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.gov
http://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpghttp://www.nature.com/nrc/journal/v3/n3/images/nrc1012-f1.jpg
http://http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmdwww.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd==Retrieve&dbRetrieve&db==pubmed&doptpubmed&dopt==Abstract&list_uidsAbstract&list_uids=12691817=12691817
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=phttp://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12427531ubmed&dopt=Abstract&list_uids=12427531http://www.biochemj.org/bj/374/0577/bj3740577.htmhttp://www.mssm.edu/jewish_genetics/genetic_diseases.shtmlhttp://www.nature.com/cgi-taf/DynaPage.taf?file=/onc/journal/v21/
n58/full/1205959a.htmhttp://tmm.trends.comhttp://www.biomedcentral.com/1471-2121/4/15