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B311 > L8, Centromeres and Telomeres > Flashcards

L8, Centromeres and Telomeres Flashcards

1
Q

How are centromeres arranged?

A
  • Constricted region of heterochromatin in each eukaryotic chromosome -> includes spindle attachment site
  • Each chromosome must have exactly one -> correct segregation without chromosome breakage
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2
Q

What 3 key components are required for kinetochore assembly -> result?

A
  • DNA sequences
  • Specialised histone variants
  • Specific proteins
  • Kinetochore -> Centromeric Chromatin
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3
Q

Give the 3 types of centromere with outline for each:

A
  • Point: 1 microtubule attaches, defined by DNA sequence, recruits specific histones
  • Regional: Not defined by specific sequences but repetitive region. Also recruit specific histones
  • Dispersed/holocentric: Recruit specific histones
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4
Q

Give the 3 types of centromere with example for each and common feature between them:

A
  • Point: budding yeast
  • Regional: Human, mouse, fission yeast
  • Dispersed/holocentric: C.elegans/nematode
  • Common feature is a replacement of histone H3 with centromere-specific histone variant CENP-A
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5
Q

Centromeres in budding yeast:

A
  • Point -> Contain short essential DNA sequences (‘CEN’)
  • CEN elements = short, conserved (CDE-I, CDE-II flank A-T rich region CDE-II) -> ~120bp total
  • The central region, CDE-II wraps around alternative nucleosome (CENP-A) -> flanking regions recruit proteins
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6
Q

+ Where is CDE-III vulnerable to mutation?

A
  • Single mutation converting CCG->CTG in CDE-III abolishes function
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7
Q

Kinetochore assembly in budding yeast:

A
  • CBF3 recruited to CDE-III (‘landing pad’)
  • Cbf1 homodimer binds CDE-I
  • Interaction of bound proteins across CDE-I, II, III with the Ctf19 complex
  • Ctf19 links the centromeric complex to kinetochore
  • (Ctf19 is one of many microtubule binding proteins involved)
  • Serve as an assembly platform for kinetochore -> connecting to single microtubule
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8
Q

Centromeres in S. pombe:

A
  • Regional -> core sequence flanked by repetitive DNA (~35-110kb in f.yeast)
  • core: cnt (wraps around multiple nucleosomes)
  • cnt is flanked by imr repeats which contain tRNA gene clusters in f.yeast
  • Both CENP-A and H3-containing nucleosomes map to the central domain, can provide landing sites for kinetochore assembly
  • Central domain flanked by left and right outer repeats (termed otr -> ‘dg’ and ‘dh’ respectively
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9
Q

Write out the order of repeat sequences in S.pombe centromeres:

A

<-dh, dg->imr->[cnt]<imr<-dg,dh->

  • dg and dh make up the otr
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10
Q

What state are regional centromeres in? Exception and relevance?

A
  • Whole structure is specified as heterochromatin
  • Lacking transcription, with the exception of inner and outer repeat regions where DNA is transcribed, producing dsRNA -> siRNAs -> heterochromatin
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11
Q

Detail the process of regional centromere formation:

A
  • Centromeric repeats transcribed by RNA PII
  • dsRNA formed via convergent transcription and RNA-dependent RNA P
  • siRNAs produced by Dicer
  • siRNAs loaded onto RITS (contains Argonaute)
  • RITS binds to nascent repeat transcripts -> recruits histone methyl transferase and RDRP -> more dsRNA
  • H3K9 methylation recruits chromodomain proteins (HP1) -> heterochromatin spreading
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12
Q

Centromeres in humans:

A
  • Made up of long arrays of simple tandem repeats (HOR of alpha-I satellite DNA of 171bp repeats )
  • Pericentromere: divergent repetitive sequences and retrotransposons (alpha-II satellite DNA)
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13
Q

What do telomeres protect against?

A
  • Prevent chromosome shortening and chromosome fusion -> unprotected end may be recognised as a DSB and ‘repaired’
  • Critical to maintain genome stability
  • Also useful in meiosis by facilitating pairing of homologous chromosomes
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14
Q

How are telomeres structured?

A
  • Telomeric repeat sequences; conserved within vertebrates and ciliates respectively
  • G rich 5’ to 3’ towards telomere
  • C rich 5’ to 3’ towards centromere
  • 3’overhang -> facilitates t-loop formation, results from post-replicative processing of C-rich strand (removing RNA primers and iDNA)
  • Variable telomere length in organisms
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15
Q

How are t-loops formed:

A
  • 3’overhand folds back around, pairs with section of other strand -> displacement loop
  • t-loop: 5-10kb
  • Catalysed by TRF2 enzyme
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16
Q

How are telomeres extended?

A
  • Telomerase (active in stem cells and cancer cells) -> ribonucleoprotein complex made up of reverse transcriptase (TERT) and an RNA template (TERC)
  • Telomerase binds to parental strand overhang, extends 3’ end (away from chromosome)
  • Lagging strand is completed by DNA pol in direction pointing back into chromosome
17
Q

What protein complex protects telomeres from damage-repair pathways and regulates their length?

List key components with role

A
  • Shelterin complex
  • Made up of 6 proteins…
  • TRF1, 2 (repeat binding)
  • Rap1 (repressor and activator)
  • POT1 (protection of telomeres)
  • TIN2, TPP1(bridging molecules)
18
Q

How does Shelterin work?

A
  • Acts to inhibit telomerase by binding repeat sequences and assembling
  • -> Telomerase inhibited
  • TERRA signals for repair
19
Q

Why is it important for telomeres to be kept heterochromatic?

A
  • They contain highly repetitive regions
  • At risk of homologous recombination -> genome instability
  • Telomeric DNA is thus sequestered by being formed into heterochromatin
20
Q

3 key marks in telomere heterochromatin:

A
  • H3K9 methylation
  • H4K20 methylation
  • HP1 binding (chromo-domain containing ‘reader’)
  • …Resembles that of pericentric chromatin
21
Q

Why can telomeric DNA not be methylated?

A
  • It has no CpG sequence
  • Conversely, sub-telomeric DNA is methylated -> degenerated repeats
22
Q

What is the function of TERRA RNAs?

A
  • Promote heterochromatin formation, facilitate DNA replication and control telomere length
  • Transcribed from the sub-telomeric sequences in a centromere-to -telomere orientation
  • Hoogsteen base pairing -> both C-rich and G-rich strand
  • Act as a scaffold molecule, promoting recruitment of proteins and enzymatic activities at telomeres; prevent binding of telomerase
23
Q

How are telomeres involved in cell senescence?

A
  • Limit cell division cycles -> Hayflick limit
  • Progressive shortening due to repressed telomerase; cell senescence eventually triggered to prevent DNA loss -> tumour suppression
  • Cancer cells do not senesce; telomerase often reactivated

B311 (12 decks)

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