Regarding the molecular mechanisms and clinical features of tumor suppressor gene inactivation, all of the following statements are correct EXCEPT:
A. WT1 (Wilms tumor suppressor) mutations cause Wilms tumor in children and are associated with WAGR syndrome (Wilms, aniridia, genitourinary abnormalities, retardation)
B. BRCA1 and BRCA2 function exclusively in mitochondrial DNA repair, explaining why their loss leads to nuclear genomic instability
C. CDKN2A/p16 inactivation (deletion or hypermethylation) removes the brake on CDK4/6, allowing uncontrolled G1/S progression independent of RB status
D. NF1 (neurofibromatosis type 1) encodes a RAS-GAP protein; loss of NF1 leads to constitutive RAS activation and neurofibromas
Explanation
Tumor Suppressor Gene Mechanisms: Distinguishing Fact from Fiction
Overview
Key Point
Tumor suppressors regulate cell cycle checkpoints, DNA repair, apoptosis, and differentiation. Understanding their specific subcellular localization and function is critical for NEET PG.
Detailed Analysis
Table
Gene
Function
Correct Statement
Status
NF1
RAS-GAP
Loss → RAS hyperactivation → neurofibromas
✓ Correct
WT1
Transcription factor
Mutations → Wilms tumor + WAGR features
✓ Correct
CDKN2A/p16
CDK inhibitor
Inactivation → CDK4/6 hyperactivity → G1/S escape
✓ Correct
BRCA1/BRCA2
Nuclear HR repair
Mitochondrial DNA repair claim
✗ Wrong
The Critical Error: BRCA Subcellular Localization
High-YieldNEET PG
BRCA1 and BRCA2 function exclusively in nuclear DNA repair, specifically homologous recombination (HR) repair of double-strand breaks (DSBs) in the nucleus.
Why This Matters:
BRCA1/BRCA2 are nuclear proteins; they do not localize to mitochondria
Their loss causes nuclear genomic instability (chromosome rearrangements, deletions, amplifications), not mitochondrial dysfunction
The mechanism of cancer predisposition is HR deficiency → unrepaired DSBs → chromosomal chaos → malignant transformation
Warning
The statement conflates:
Mitochondrial DNA repair (not BRCA function)
Nuclear DNA repair (correct BRCA function)
This is a classic distractor designed to test whether students understand subcellular localization of repair machinery.
Why the Other Options Are Correct
1.
NF1: Encodes neurofibromin, a RAS-GAP protein. Loss → RAS remains in active GTP-bound state → uncontrolled growth → neurofibromas and increased malignancy risk.
2.
WT1: Wilms tumor suppressor; mutations cause:
Wilms tumor (embryonal kidney cancer)
WAGR syndrome (contiguous gene deletion including WT1 and PAX6)
Denys-Drash syndrome (WT1 point mutations + genitourinary dysgenesis)
3.
CDKN2A/p16: CDK inhibitor that binds CDK4/6, preventing their interaction with cyclin D. Loss removes this checkpoint → CDK4/6 hyperactivity → RB hyperphosphorylation → uncontrolled S-phase entry, even if RB is intact.
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