1.Variants in the PALB2 gene are associated with an increased risk of developing breast cancer [5] and PALB2-deficient cells are sensitive to PARP inhibitors. [4]
PALB2 was recently identified as a susceptibility gene for familial pancreatic cancer
by scientists at the Sol Goldman Pancreatic Cancer Research Center at
Johns Hopkins. This has paved for the way for developing a new gene test
for families where pancreatic cancer occurs in multiple family members.[6] Tests for PALB2 have been developed by Ambry Genetics [7]and Myriad Genetics[8] that are now available through a genetic counselor.
Biallelic mutations in PALB2 (also known as FANCN), similar to biallelic BRCA2 mutations, cause Fanconi anemia.[3]wikipedia
2 xia et al: described superbly the role of PALB2
" the identification of PALB2, a BRCA2 binding protein. PALB2 colocalizes
with BRCA2 in nuclear foci, promotes its localization and stability in
key nuclear structures (e.g., chromatin and nuclear matrix), and enables
its recombinational repair and checkpoint functions. In addition,
multiple, germline BRCA2 missense mutations identified in breast cancer
patients but of heretofore unknown biological/clinical consequence
appear to disrupt PALB2 binding and disable BRCA2 HR/DSBR function.
Thus, PALB2 licenses key cellular biochemical properties of BRCA2 and
ensures its tumor suppression function."
3. And has mentioned hematologic complication is not very far!
" Fanconi anemia is a rare, recessive, chromosomal instability disorder
characterized by growth retardation, congenital malformations,
progressive bone marrow failure, cancer predisposition and cellular
hypersensitivity to DNA cross-linking agents1.
The syndrome is genetically heterogeneous with 12 complementation
groups currently recognized, 11 of which have been attributed to
distinct genes: FANCA (FA-A), FANCB (FA-B), FANCC (FA-C), BRCA2 (FA-D1), FANCD2 (FA-D2), FANCE (FA-E), FANCF (FA-F), FANCG (FA-G), BRIP1 (FA-J), FANCL (FA-L) and FANCM (FA-M)2, 3." Sarah Reid et al....
4. And the devastation does not stop to Fanconi and Breast cancer!
ERKKO et al:
"These results indicate that PALB2 is a breast cancer
susceptibility gene that, in a suitably mutant form, may also contribute
to familial prostate cancer development." in a Finnish population
SIAN JONES ET AL
"the role of PALB2 as a susceptibility gene for pancreatic cancer. PALB2 mutations have been previously reported in patients with familial breast cancer, and the PALB2 protein is a binding partner
for BRCA2. "
SOME AUTHORS ADD GALLBLADDER,MELANOMA AND GASTRIC CANCERS TO THIS SAD LITANY.
====================================================================
6.RAD51
"In humans, RAD51 is a 339-amino acid protein that plays a major role in homologous recombination
of DNA during double strand break repair. In this process, an ATP
dependent DNA strand exchange takes place in which a template strand
invades base-paired strands of homologous DNA molecules. RAD51 is
involved in the search for homology and strand pairing stages of the
process.
Unlike other proteins involved in DNA metabolism, the RecA/Rad51 family forms a helical nucleoprotein filament on DNA.[2]
This protein can interact with the ssDNA-binding protein RPA, BRCA2, PALB2[3] and RAD52."WIKIPEDIA
RAD 51 KEEPS BAD ASSOCIATIONS, BROADENING THE DANGER!
" RAD51 has been shown to interact with BRE,[12] RAD54B,[13] Ataxia telangiectasia mutated,[14] BRCC3,[12] BARD1,[12] BRCA2,[12][15][16][17][18][19][20][21][6][22][23][24][25] UBE2I,[26][27] Abl gene,[14] BRCA1,[12][24][28][29] ATRX,[13][30] RAD52,[14] DMC1,[31] P53[12][32][33] and Bloom syndrome protein.[34]"WIKIPEDIA
====================================
ON TOP OF ALL THIS
YOU STILL HAVE
- CDH1
- p53 MUTATIONS
- PTEN
OUR WORK IS CUT OUT TO TRAVEL THIS MAZE!
RTEL1 Is a Replisome-Associated Helicase That Promotes Telomere and Genome-Wide Replication
- Jean-Baptiste Vannier1,*,
- Sumit Sandhu2,*,
- Mark IR. Petalcorin1,
- Xiaoli Wu2,
- Zinnatun Nabi2,
- Hao Ding2,3,†,
- Simon J. Boulton1,†
+ Author Affiliations
- ↵†Corresponding author. E-mail: dingh@cc.umanitoba.ca (H.D.); simon.boulton@cancer.org.uk (S.J.B.)
-
↵* These authors contributed equally to this work.
Regulator of telomere length 1 (RTEL1)
is an essential DNA helicase that disassembles telomere loops (T loops)
and suppresses
telomere fragility to maintain the integrity of
chromosome ends. We established that RTEL1 also associates with the
replisome
through binding to proliferating cell nuclear
antigen (PCNA). Mouse cells disrupted for the RTEL1-PCNA interaction
(PIP mutant)
exhibited accelerated senescence, replication
fork instability, reduced replication fork extension rates, and
increased origin
usage. Although T-loop disassembly at telomeres
was unaffected in the mutant cells, telomere replication was
compromised,
leading to fragile sites at telomeres. RTEL1-PIP
mutant mice were viable, but loss of the RTEL1-PCNA interaction
accelerated
the onset of tumorigenesis in p53-deficient
mice. We propose that RTEL1 plays a critical role in both telomere and
genome-wide
replication, which is crucial for genetic
stability and tumor avoidance.
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PLEASE GO TO THE FULL ARTICLE,
GOOD JOB FOR THESE SCIENTISTS!
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PLEASE GO TO THE FULL ARTICLE,
GOOD JOB FOR THESE SCIENTISTS!
