Chromosome instability and tumor predisposition inversely correlate with BLM protein levels.
Independent mouse models for Bloom syndrome (BS) exist, each thought to disrupt Blm gene function. However, animals bearing these alleles exhibit distinct phenotypes. Blm(tm1Ches) and Blm(tm1Grdn) homozygous mutant animals exhibit embryonic lethality while in another, Blm(tm3Brd), homozygosity yields viable, fertile animals with a cancer predisposition. Further characterization reveals the Blm(tm3Brd) allele to be a hypomorph, producing a diminished quantity of normal mRNA and protein. The Blm(tm3Brd) allele produces sufficient normal protein to rescue Blm(tm1Ches) lethality. Evaluation of viable animals reveals an inverse correlation between the quantity of Blm protein and the level of chromosome instability and a similar genotypic relationship for tumor predisposition indicating that Blm protein is rate limiting for maintaining genomic stability and the avoidance of tumors.
McDaniel
Lisa D
LD
Department of Pathology, CY1.107, UT Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-8840, USA.
Chester
Nicholas
N
Watson
Mark
M
Borowsky
Alexander D
AD
Leder
Philip
P
Schultz
Roger A
RA
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001816:Bloom Syndrome / Q000235:genetics*; D043171:Chromosomal Instability; D004265:DNA Helicases / Q000378:metabolism*; D020964:Embryo Loss / Q000235:genetics; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005260:Female; D018390:Gene Targeting; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053484:RecQ Helicases; D013154:Spleen / Q000378:metabolism; D013489:Suppression, Genetic
D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; C097151:Bloom syndrome protein; D004265:DNA Helicases; D053484:RecQ Helicases