Fanconi anaemia lecture 14

Question 1

List some clinical phenotype

Answer 1

Microcephaly, Mental retardation, Developmental delay, Skin pigmentation complex, Hypoplastic thumbs, Aplastic anaemia, Predisposition to tumour development ,Bone marrow failure

Question 2

Describe the genetics of fanconi anaemia

Answer 2

Autosomal recessive

Apart from FANCB which is X-linked 18 identified genes designated FANCA-FANCT (no FANCH or FANCK)

FANCA,C,G are the most common

FANCD1- mutation in both BRCA2

FANCN- mutation in both PALB2

FANCS- mutation in both BRCA1

Question 3

What are the cancers that FA patients are suseptable to?

Answer 3

Myelodysplastic syndrome (MDS)

Acute myeloid leukaemia (AML)

Adult patients that have received bone marrow transplants are predisposed to head/neck, gynaecological and/gastrointestinal tumours

FANCD1, FANCN, FANCS complementation groups are suseptable to breast/ovarian cancers

FANCD1 also AML, T cell acute lymphocytic leukaemia (T-ALL), Wilms’ tumour, medulloblastoma and GBM

Question 4

What is the significance of the FANC genes in normal physiology?

Answer 4

Involved in the interstrand cross link (ICL) repair pathway

Two strands are covalently linked, causing the 1st replication fork to arrive and stall

2nd fork converges at ICL and helicase falls off

FA core complex activates and ubiquitylates FANCD2 and FANCI, which then sit on the linked DNA

These recruit nucleases which make two cuts on the same strand. FANCD2 and FANCI are the deubiquitylated and dissociate

The ICL is now only attached to one strand so Bypass polymerase replicates past it

HR machinery is then recruits and the broken strand is repaired

HJ resolution then occurs

Question 5

How does FA result in genome stability?

Answer 5

ICLs means that the DNA cannot be completely replicated

Hemi-catenated DNA cannot be separated during anaphase creating an anaphase bridge

After division the DNA breaks off, often at common fragile points (CFPs) from the rest and forms either nuclear bridging or micro nuclei, these can accumulate into a mitotic catastrophe

Increased chromosome breakage with an impaired HR pathway means that the cell attempts to repair it with NHEJ resulting in radial chromosomes which contribute to mitiotic catastrophe

Question 6

What is the endogenous legion repaired by FA proteins?

Answer 6

Reactive intermediates- aldehydes, can produce ICL and DNA-protein crosslinks A

cetaldehyde is a byproduct of alcohol metabolism and an intermediate of carbohydrate metabolism

Formaldehyde is a byproduct of DNA and histone demethylation, the biosynthesis of purines and certain AAs and found in tabacco smoke, e-cigarettes, aspartame and methanol

Alcohol dehydrogenase- ALD5 Aldehyde dehydrogenase- ALDH2

Anaphase bridging in Fanconi Anaemia can be corrected by

Corrected by inhibition of NHEJ, as ICLs are mis-repaired by it leading to chromosomal fusions

-These aberrant chromosomal structures contribute to tumour development in FA patients through activation of oncogenes or inactivation of tumour suppressor genes