A 13-year-old boy with growth retardation, microcephaly, sun-sensitive skin rash, and recurrent infections is being evaluated for a possible inherited genetic defect. The patient is the second-born child of a first cousin marriage. His parents and siblings are healthy, but 2 of his maternal cousins have similar signs and symptoms. Genetic analysis of the patient reveals a defect in the BLM gene that codes for DNA helicase. Which of the following is the most likely site of action of this enzyme in the DNA replication fork shown below?

Question

A 13-year-old boy with growth retardation, microcephaly, sun-sensitive skin rash, and recurrent infections is being evaluated for a possible inherited genetic defect.  The patient is the second-born child of a first cousin marriage.  His parents and siblings are healthy, but 2 of his maternal cousins have similar signs and symptoms.  Genetic analysis of the patient reveals a defect in the BLM gene that codes for DNA helicase.  Which of the following is the most likely site of action of this enzyme in the DNA replication fork shown below?

Quizplus · Accepted Answer

11ec160b_3763_04b6_9249_c1cbaa5504ed_MD0001_00 This patient has Bloom syndrome, a rare autosomal recessive disorder caused by mutations in the BLM gene. This gene encodes DNA helicase, an enzyme responsible for unwinding of the double helix during DNA replication and repair. Helicase dysfunction results in chromosomal instability and breakage and manifests clinically with growth retardation, facial anomalies (eg, microcephaly), photosensitive rash, and immunodeficiency (eg, recurrent infections). DNA replication occurs during the S phase (synthesis phase) of the cell cycle and is coordinated by the effects of multiple proteins. First, the origin of replication is identified and bound by a multi-subunit protein (the origin recognition complex), which locally dissociates double-stranded DNA (dsDNA) into single-stranded DNA (ssDNA). ssDNA-binding proteins then bind to and stabilize the ssDNA, preventing it from reannealing (Choice C). Helicase subsequently binds to ssDNA at the origin of replication, moves into the replication fork, and proceeds to separate and unwind the dsDNA. As DNA is unwound, superhelical tension is generated as supercoils are being formed. Topoisomerase relieves this tension by introducing transient single- or double-stranded nicks in the DNA. This enzyme is located ahead of helicase on the dsDNA segment of the replication fork (Choice A). (Choice D) Before DNA polymerase can begin synthesizing DNA, it requires an RNA primer made up of short RNA sequences base-paired to the parent DNA. This primer is synthesized by the enzyme primase (DNA-dependent RNA polymerase). (Choice E) DNA polymerase synthesizes new daughter strand DNA in the 5' to 3' direction. The leading strand is formed continuously, whereas the lagging strand is formed discontinuously, creating Okazaki fragments. (Choice F) Okazaki fragments are ultimately bound together by the enzyme ligase. Educational objective: Bloom syndrome is a rare autosomal recessive condition caused by mutations in the BLM gene encoding helicase, an enzyme that unwinds the double helix during DNA replication. Patients typically present with growth retardation, facial anomalies, photosensitive skin rash, and immunodeficiency due to chromosomal instability and breakage. __________ References: Clinical features of Bloom syndrome and function of the causative gene, BLM helicase. (http://www.ncbi.nlm.nih.gov/pubmed/15137905) The replication fork: understanding the eukaryotic replication machinery and the challenges to genome duplication. (http://www.ncbi.nlm.nih.gov/pubmed/23599899)

A 13-Year-Old Boy with Growth Retardation, Microcephaly, Sun-Sensitive Skin Rash