The stability of the cellular genome is constantly threatened by a variety of exogenous and endogenous mutagenic agents such as UV light,

reactive oxygen species, etc.

Cells protect their genome against carcinogenic alterations by using a complex network of caretaker proteins that function to maintain the integrity of the cellular chromosomes.
Inherited defects in these caretaker genes are the cause of genomic instability syndromes in

 An increased tendency of the GENOME to acquire MUTATIONS when various processes involved in maintaining and replicating the genome are dysfunctional. Cellular
DNA damage metabolis m Routine errors in DNA replication & recombination

We study these diseases to understand and discover novel mechanisms important to control and suppress cancer susceptibility.

induces cell cycle arrest Response system -activates the appropriate DNA repair pathway induces apoptosis

Mutations in the genes that encode DNA damage response proteins can result in a number of genomic instability syndromes, disorders that often result in a heightened predisposition to cancer.

 Loss of a bases- Results in apurinic/apyrimidinic (AP) sites (abasic sites); Base modifications-Alkylations or deamidations

Causes
Photo damage by UV light

Errors
CPDs Pyrimidine(6-4) Purimidone photoproducts(6-4PPs)

Chemical agents & ROS Replication errors & base conversions

Modify bases Mismatch nucleotide pairs

Failures in normal DNA metabolism Ionizing radiation

Single strand and double strand breaks

HRR: Synthesis- dependent strand annealing Single- strand annealing NHEJ: Direct modification & ligation of 2 DNA ends in DSB.

Removes Incorrect/damaged bases

Recognizes abnormal structures

MISMATCHES LOOPS

 DNA DSBs represent the most serious DNA damage, which, if not repaired accurately, can result in genomic instability, including chromosome rearrangements or gene mutations, and finally can lead to cancer defects in the genes encoding ATM, NBN (NBS1), BRCA1, FANCD2, BLM, TP53, CDS1/CHK2, and others, can cause

MUTATIO N

FANCONI ANEMIA

 Fanconi anemia (FA), is a rare, blood disorder that leads to bone marrow failure. Acquired or Inherited Prevents bone marrow from making enough new blood Can affect many of your body's organs, tissues, and systems Autosomal recessive disorder Heterozygote frequency- 1 in 300

Skin hyperpigmentatio n Increased cafau-lait spots Short stature Skeletal abnormalities

Microcephaly or micrognathia Low birth weight Retardation Ear abnormalities GI tract abnormalities

Deficient in their ability to excise UVinduced pyrimidine dimers from their DNA DNA crosslink repair deficiency is responsible for chromosomal damage in this disorder. Cellular defect in FA results in chromosomal instability, hypersensitivity to DNA damage, and hyper mutability thus predisposing to leukemia as a multistep process

MHF1 and MHF2 - work together to bind to specific DNA structures and are "indispensable for the functional integrity of the FA pathway.
The proteins were identified working through a specific core component protein of the FA pathway called FANCM, one of eight currently known to make up the FA core complex. MHF1 and MHF2 help FANCM prevent or repair Interstrand crosslinks, which if unresolved can lead to cell defects and disease

Loss of MHF1 alone disrupts normal function of

SYNDRO ME Fanconi A

GENE FANC A

LOCATIO N 16q 243 9q 223

PRODUCT DNA repair DNA repair

Fanconi C FANC C Fanconi D FANC D Fanconi E FANC E

3p22- p26 DNA repair 6p21- p22 DNA repair

Fanconi G FANC G

9p13

Post replication repair

In vitro enhancement of chromosome breakage by DEB and mitomycin C

Bone Marrow Transplantation from an HLA compatible sibling. Gene therapy Published studies indicate it is possible to insert the cloned FANC-C and FANC-A gene into hematopoietic FA stem cells and provide protection against clastogenic agents.

ATAXIA MUTATION TELANGIE CTASIA

Immunodeficienc y disorder Autosomal recessive disorder Affect central nervous & immune systems Cerebellar

Radiation sensitivity Cell cycle abnormalities Chromosomal instability Predisposition to leukemias & lymphomas

Sole gene responsible for this disorder 66 exons 11q22-23 12kbp Protein- 350 kD ATMs activity increases following DSBs

 The activation of atm is only partially understood, but it involves auto or trans phosphorylation of serine in response to DNA DSBs and may require protein phosphatase 5 activity. Breaks in genome leading to rapid activation of entire ATM- chain reaction occurs- active ATM monomers releasedphosphorylate inactive ATM dimers. Phosphorylation of TP53 by ATM occurs on Ser15 Stabilization of Tp53 is induced by ATM

recurrent infections and typical immunologic findings Elevation of serum alpha- fetoprotein levels Micronucleus test Detection of the protein (ATM) made by the A-T gene using a western blot Measurement of cellular damage (cell death or chromosomal breakage) after exposure of cells to x-rays in the laboratory Sequencing (reading the spelling) of the A-T gene (ATM)

MUTATIO N NBS NBS/MRE11/R AD50

Rare autosomal recessive disorder Microcephaly A distinct facial appearance Short stature Immunodeficiency Radiation sensitivity A strong predisposition to lymphoid malignancy

 Nijmegen breakage syndrome is caused by mutations in the NBN/NBS1 gene located at 8q21. The entire gene consists of 16 exons and spans a DNA region of more than 50 kilobases. NBN gene product(nibrin)- interact-, hMre11 and Rad50. Nibrin- regulates the activity of the M/R/N protein complex- end-processing of both

 DNA DSBs occur as intermediates in physiological events, such as recombination during early B- and T-cell development and immunoglobulin class switch in mature B cells, but most frequently are generated by mutagenic agents such as IR and radiomimetic chemicals

Consanguineous matings have been

 The diagnosis is based on the characteristic phenotype and laboratory results. Laboratory studies helpful in diagnosing Nijmegen breakage syndrome include cytogenetic analysis, an evaluation of humoral and cellular immunity, and radiation-sensitivity testing. Molecular genetic analysis enables definite confirmation.

 No specific therapy is available for Nijmegen breakage syndrome (NBS).

 Malignancy is the most common cause of death in patients with Nijmegen breakage syndrome.
Other known causes of death are fatal infections leading to respiratory failure, renal or liver insufficiency, and bone marrow aplasia (aplastic anemia).

MUTATIO N

 Rare autosomal recessive disorder Characterized by telangiectases and photosensitivity growth deficiency of prenatal onset Variable degrees of immunodeficiency Increased susceptibility to neoplasms of many sites and types. The New York dermatologist David Bloom first described the syndrome in 1954.

 Mutation BLM gene- Chromosome 15q26.1 DNA helicase activity and functions in the maintenance of genomic stability Increased sister chromatid exchanges and chromosomal instability also occur BLM variants & proteins that form complexes with BLM (eg, TOP3A, RMI1) Increases cancer risk Mutation- DNA ligase I gene- primary metabolic defect in Bloom

 Chromosome study- blood and skin cells show a characteristic pattern of chromosome breakage and rearrangement. Testing for chromosome instabilityincludes the presence of quadriradicals and increased sister chromatid exchanges Decreased immunoglobulin A and immunoglobulin M levels

 Increased risk of premature death in the second or third decade occurs secondary to malignancies. Various types of leukemia develop at a mean age of 22 years. Patients who survive beyond age 22 years develop solid tumors at an average age of 35 years. Fortunately, these tumors are sensitive to

 poikiloderma congenitale photosensitivity and poikilodermatous skin changes juvenile cataracts skeletal dysplasias predisposition to osteosarcoma and skin cancer.

 Mutations- RECQL4 geneChromosome 8q24 Encodes a RecQ DNA helicase. RecQ helicases - DNA replication and repair Essential for the maintenance of genomic stability Presence of truncating, loss-of-

 Bloom Syndrome (Congenital Telangiectatic Erythema) Dyskeratosis Congenita Erythropoietic Protoporphyria Lupus Erythematosus, Acute

Baseline skeletal radiographs of the long bones by age 5 -high frequency of skeletal dysplasias

 Otto Werner originally defined Werner syndrome (WS) in 1904 WS is also known as progeria adultorum, progeria of the adult, and pangeria. Most common of the premature aging disorders Autosomal recessive disorder that affects connective tissue throughout

 Caused by a mutation at the WS gene (WRN) locus, which belongs to the family of RecQ helicases involved in the response to DNA damage during replication, as well as in the transcription processes. Excessive synthesis of collagen types I and III

 WS is a rare disorder. United States- 1 case in 1 million individuals. WS has no specific laboratory abnormalities

Damage recognition Binding of a multi-protein complex at the damaged site Double incision of the damaged strand several nucleotides away from the damaged site, on both the 5' and 3' sides Removal of the damage-containing oligonucleotide from between the two nicks Filling in of the resulting gap by a DNA

severe light sensitivity frequent neurological defects severe pigmentation irregularities early onset of skin cancer at high incidence elevated frequency of other forms of cancer

 United States- 1 case per 250,000 population. Group XPC is the most common form in the United States.

 No consistent routine laboratory abnormalities are present in xeroderma pigmentosum patients. The diagnosis of xeroderma pigmentosum can be established with studies performed in specialized laboratories. These studies include cellular hypersensitivity to UV radiation and chromosomal breakage studies, complementation studies, and gene

 The goal of treatment is to protect the patient from sunlight The use of sunscreens in conjunction with other sun-avoidance methods (eg, protective clothing, hats, eyewear) can minimize UV-induced damage in patients with xeroderma pigmentosum.

Features light sensitivity in some cases neurological abnormalities premature aging of some tissues facial and limb abnormalities dwarfism thinning of the skin and hair

Complications Mental RetardationGrowth failure Progressive pigmentary retinopathy Sensorineural hearing loss Joint contractures and ataxia Hypertension Photosensitivity

Cockayne syndrome type 1- the classic form; Cockayne syndrome type 2- a more severe form with symptoms present at birth Cockayne syndrome type 3- a milder form; FREQUENC US- 1 in 2,50,000 LIVE BIRTHS Y xeroderma pigmentosa

 CKN1- defect-CSA gene or ERCC8chromosome 5. Cells- ERCC8 mutations hypersensitive to UV light. They do not recover the ability to synthesize RNA . They cannot remove and degrade DNA lesions from strands that have active transcription.

 Encodes helicase- DNA unwinding function. Mutations deletion of exon 4 an amino acid substitution at the 106th glutamine to proline (Q106P) in the WD-40 repeat motif of the CSA protein large deletion in the upstream region, including exon 1 of the CSA gene. a missense mutation (A205P) and a nonsense (E13X) mutation have been

 Chromosome breakage studies and DNA mutation analysis are necessary to exclude Bloom syndrome and xeroderma pigmentosum. Cultured skin fibroblasts of patients with CKN1 lack the ability

 CT scan or MRI findings include increased ventricular size, cerebral atrophy, white matter abnormalities, and normal pressure hydrocephaly. Skeletal radiographs depict vertebral body and pelvic abnormalities.

SUMMARY